Nociception Research Papers - Academia.edu (original) (raw)

The aim of the study was to evaluate the therapeutic effect of electro-acupuncture (EA) and hydrotherapy, both in combination with patient education or with patient education alone, in the treatment of osteoarthritis in the hip.

In this paper we review the currentneurophysiological modelsof touch-evokedpain and present a new proposalthat addressesthe mechanismsof allodynia.The new modelis basedon the notionthat A-p mechartoreceptors can gain accessto nociceptive... more

In this paper we review the currentneurophysiological modelsof touch-evokedpain and present a new proposalthat addressesthe mechanismsof allodynia.The new modelis basedon the notionthat A-p mechartoreceptors can gain accessto nociceptive neuronesby meansof a presynapticlink, at centrallevel,betweenlow thresholdmechanoreceptors and nociceptors,We proposethat the excitationof nociceptorsprovokedby a peripheralinjury activatesthe spinalintemeuronesthat mediateprimaryafferentdepolarization (PAD)betweenlow thresholdmechanoreceptors and nociceptors.As a consequenceof the increasedand persistentbarragedrivingthese neuronestheir excitabilityis increasedsuch that, whenactivatedby low thresholdmechanoreceptors from areas surroundingthe injury site, they producea very intensePADin the nociceptiveafferentswhichis capableof generatingspike activity.This activationwouldbe conductedantidromicallyin the formof dorsalrootreflexes(DRRs)but wouldalsobe conductedforwardactivatingthe secondorderneurones normallydriven by nociceptors.The sensoryconsequenceof this mechanismis pain evokedby the activationof low threshold mechanoreceptors froman area surroundingan injurysite (allodynia),

Hyperpolarizing fast inhibitory neurotransmission by c-aminobutyric acid and glycine requires an efficient chloride extrusion mechanism in postsynaptic neurons. A major effector of this task in adult animals is the potassium-chloride... more

Hyperpolarizing fast inhibitory neurotransmission by c-aminobutyric acid and glycine requires an efficient chloride extrusion mechanism in postsynaptic neurons. A major effector of this task in adult animals is the potassium-chloride co-transporter KCC2 that is selectively and abundantly expressed postsynaptically in most CNS neurons. Yet, the role of KCC2 in adult brain at the systems level is poorly known. Here, we characterize the behaviour of mice doubly heterozygous for KCC2 null and hypomorphic alleles that retain 15-20% of normal KCC2 protein levels in the brain. These hypomorphic KCC2-deficient mice were viable and fertile but weighed 15-20% less than wild-type littermates at 2 weeks old and thereafter. The mice displayed increased anxiety-like behaviour in several tests including elevated plus-maze and were more susceptible to pentylenetetrazole-induced seizures. Moreover, the mice were impaired in water maze learning and showed reduced sensitivity to tactile and noxious thermal stimuli in von Frey hairs, hot plate and tail flick tests. In contrast, the mice showed normal spontaneous locomotor activity in open field and Y-maze tests, and intact motor coordination in rotarod and beam tests. The results suggest that requirements for KCC2-dependent fast hyperpolarizing inhibition may differ among various functional systems of the CNS. As shunting inhibition is expected to be intact in KCC2-deficient neurons, these mice may provide a useful tool to study the specific functions and relative importance of hyperpolarizing fast synaptic inhibition in adult CNS that may have implications for human neuropsychiatric disorders, such as epilepsy, pain and anxiety.

The barks of Drimys winteri are used in folk medicine as a remedy to treat several diseases, including dolorous processes. Previous pre-clinical experiments carried out in our laboratories revealed that the hydroalcoholic extract of this... more

The barks of Drimys winteri are used in folk medicine as a remedy to treat several diseases, including dolorous processes. Previous pre-clinical experiments carried out in our laboratories revealed that the hydroalcoholic extract of this plant showed anti-allergenic, anti-inflammatory and antinociceptive properties. Such promising results led us to determine the analgesic compounds present in D. winteri. Through conventional chromatographic procedures with fractions of CH 2 Cl 2 and EtOAc obtained from methanolic extract, it was found that polygodial (1), 1-i-(p-methoxycynnamyl) polygodial (2), taxifolin (3) and astilbin (4), are the main components of these fractions. Compounds 1 and 2 exhibited marked antinociceptive action by intraperitoneal and oral routes against acetic acid-induced abdominal constrictions in mice, suggesting that they are responsible, at least partially, for the antinociceptive effects of this plant. In addition, both compounds were notably more potent than aspirin and acetaminophen, two well-known drugs used here as comparison.

Mice with a targeted disruption of adenosine A 3 receptor (A 3 AR) gene were assessed for their nociceptive threshold and for their localized in£ammatory response following carrageenan injected into the hindpaw. Under basal conditions no... more

Mice with a targeted disruption of adenosine A 3 receptor (A 3 AR) gene were assessed for their nociceptive threshold and for their localized in£ammatory response following carrageenan injected into the hindpaw. Under basal conditions no di¡erence was seen between A 3 AR knockout (A 3 AR 3/3) and wild-type (A 3 AR +/+) mice in nociceptive response to mechanical or heat stimuli. The antinociceptive response to the intrathecal adenosine analogue R-phenylisopropyl adenosine (R-PIA) was also unchanged in the A 3 AR 3/3 mice. In contrast, heat hyperalgesia, plasma extravasation and edema following carrageenan-induced in£ammation in the hind paw were signi¢cantly reduced in A 3 AR 3/3 mice compared to the A 3 AR +/+ controls. Thus, mice lacking A 3 AR had de¢cits in generating the localized in£ammatory response to carrageenan, supporting a pro-in£ammatory role of A 3 AR in peripheral tissues. However, no evidence for a role of A 3 AR in nociception and the antinociceptive e¡ect of R-PIA was found.

The aim of the present study was to test (1) whether muscle pain is influenced by temporal and spatial summation, and (2) whether sequential noxious muscle stimuli applied at hourly interstimulus-intervals could produce an increased... more

The aim of the present study was to test (1) whether muscle pain is influenced by temporal and spatial summation, and (2) whether sequential noxious muscle stimuli applied at hourly interstimulus-intervals could produce an increased sensation of pain due to central hyperexcitability. In the study eleven healthy men were exposed to computer-controlled intramuscular infusion of saline (5%) given over 20 s in m. tibialis anterior (m. TA). The intensities of local and referred pain were assessed by recordings on visual analogue scales (VAS), and the areas of local pain (around the injection site) and referred pain (outside the local pain area) were localised by the subject. Three experiments were performed. Experiment 1: Each subject participated in three tests separated by one week: (a) bolus (0.4 ml saline) infusion at one site; (b) four sequential infusions (0.1 ml saline) given at 90-s interstimulus-intervals at one site; and (c) four sequential infusions (0.1 ml saline) given at 360-s interstimulus-intervals at one site. Experiment 2: This was performed as experiment 1, but the infusions were given at spatially separated sites. Experiment 3: Hypertonic saline (0.1 ml) was injected one, four and 24 h after the sequential infusions (90-s interstimulus-intervals) given at spatially separated sites. The highest VAS peak and the largest local and referred pain areas were found after the bolus infusions. Compared to the first infusion, significant increases were found in the VAS peak, the size of the local pain area, and the size of the referred pain area (non-significant) after the four sequential infusions given at 90s interstimulus-intervals (temporal summation). Four spatially separated infusions given simultaneously produced a higher VAS peak, a larger local pain area, and a larger referred pain area (non-significant) compared to one infusion (spatial summation). The infusion given 4 h after the sequential infusions tended to produce an increase in the referred pain area and in the pain intensity. In all three experiments significant correlations were found between the VAS peak and the size of the local (R = 0.64, P Ͻ 0.0001, n = 231) and referred (R = 0.47, P Ͻ 0.0001, n = 231) pain areas. Based on the above results it can be concluded that experimental muscle pain is influenced by temporal and spatial summation.

The International Association for the Study of Pain (IASP) defines pain as ''an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage''. Pain may also be... more

The International Association for the Study of Pain (IASP) defines pain as ''an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage''. Pain may also be experienced in absence of noxious stimuli and together with temperature and other bodily feelings constitute the interoception redefined as the sense of the physiological condition of the entire body, not just the viscera. The main characteristic of these feelings is the affective aspect. Emotion, motivation, and consequent behavior connected with these feelings characterize their homeostatic role. This implies an interaction between neural structures involved in pain sensation and autonomic control. The aim of this review is to focus on pain perception, mainly on pain matrix structures' connections with the autonomic nervous system.

Background: Pain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas. Objectives: This review provides an overview of our current... more

Background: Pain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas. Objectives: This review provides an overview of our current knowledge, with emphasis on current pain management strategies and recent experimental findings. Methods: A systematic search of the scientific literature was carried out using EMBASE, PubMed/MED-LINE, and the Cochrane Central Register of Controlled Trials for the years 1965e2011 to obtain access to all publications, especially randomized controlled trials, systematic reviews, and meta-analyses exploring pain and its management in disease states such as acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer (PC). Results: Over the last decade, numerous molecular mediators such as nerve growth factor and the transient receptor potential (TRP) cation channel family have been implicated in afferent nerve signaling. More recent animal studies have indicated the location of the receptive fields for the afferent nerves in the pancreas and shown that these are activated by agents including cholecystokinin octapeptide, 5hydroxytryptamine and bradykinin. Studies with PC specimens have shown that neuro-immune interactions occur and numerous agents including TRP cation channel V1, artemin and fractalkine have been implicated. Experimental studies in the clinical setting have demonstrated impairment of inhibitory pain modulation from supraspinal structures and implicated neuropathic pain mechanisms. Conclusions: Our knowledge in this area remains incomplete. Characterization of the mediators and receptors/ion channels on the sensory nerve terminals are required in order to facilitate the development of new pharmaceutical treatments for AP and CP.

Stimulation of nicotinic acetylcholine receptors (nAChR) excites peripheral sensory nerve fibres, but also exert antinociceptive effects. The differences in these nAChR-mediated effects could be related to the expression of different... more

Stimulation of nicotinic acetylcholine receptors (nAChR) excites peripheral sensory nerve fibres, but also exert antinociceptive effects. The differences in these nAChR-mediated effects could be related to the expression of different nAChR subtypes located on nociceptive neurons. In the present study, we focused on the recently described a10-nAChR subunit, and on a4 and a7 subunits, which are the most abundant subunits in the central nervous system. In nociceptive neurons from thoracic and lumbar dorsal root ganglia (DRG), nAChR subunits were found at transcriptional (RT-PCR), translational (immunohistochemistry) and functional levels. Cultured DRG neurons express mRNA for the subunits a2-7 and a10. The a-subunit proteins 4, 7 and 10 were colocalised in virtually all nociceptive neurons that were identified by immunoreactivity for the vanilloid receptor TRPV-1. These findings were corroborated by current recordings and calcium measurements, which revealed excitatory inward currents and calcium responses in capsaicin sensitive neurons.

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently, functional imaging studies have shown... more

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently, functional imaging studies have shown that limbic structures like the anterior cingulate cortex and amygdala are also implicated. Since these structures are involved in learning processes, it is possible that the HNCS-induced pain inhibition may depend on specific cues from the environment that have been associated with pain reduction through associative learning. We investigated the influence of Pavlovian conditioning on HNCS-induced pain inhibition in 32 healthy subjects by using a differential conditioning paradigm in which two different acoustic stimuli were either repeatedly paired or unpaired with HNCS. Series of noxious electrical pulse trains delivered to the non-dominant foot served as test stimuli. Diffuse noxious inhibitory control (DNIC)like effects were induced by concurrent application of tonic HNCS (immersion of the contralateral hand in ice water). Subjective pain intensity and pain unpleasantness ratings and electromyographic recordings of the facial corrugator muscle and the nocifensive RIII flexion reflex were used to measure changes in pain sensitivity. HNCS induced significant pain and reflex inhibitions. In the post-conditioning phase, only the paired auditory cue was able to significantly reduce pain perceptions and corrugator muscle activity. No conditioned effect could be observed in RIII reflex responses. Our results indicate that the functional state of endogenous pain control systems may depend on associative learning processes that, like in the present study, may lead to an attenuation of pain perception. Similar albeit opposite conditioning of pain control mechanisms may significantly be involved in the exacerbation and chronification of pain states.

Cannabinoids modulate nociceptive processing through central and peripheral mechanisms. The present study was conducted to evaluate axonal flow of cannabinoid receptors from the dorsal root ganglion to the periphery and to identify the... more

Cannabinoids modulate nociceptive processing through central and peripheral mechanisms. The present study was conducted to evaluate axonal flow of cannabinoid receptors from the dorsal root ganglion to the periphery and to identify the putative involvement of CB 1 and/or CB 2 receptor subtypes. The sciatic nerve was tightly ligated to dam the flow of cannabinoid receptors to the periphery. The densities of cannabinoid receptors proximal and distal to one or two tightly constrictive ligatures was evaluated using in vitro receptor binding and high-resolution emulsion autoradiography. In both models, [ 3 H]CP55,940 binding accumulated proximal as opposed to distal to the ligature. These data indicate that axonal transport of cannabinoid receptors to the periphery was occluded by tight constriction of the sciatic nerve. In situ hybridization histochemistry revealed that dorsal root ganglia cells synthesize CB 1 but not CB 2 receptor messenger RNA. By contrast, CB 2 messenger RNA was highly expressed in sections of rat spleen that were processed together with the dorsal root ganglia, as previously described. These data demonstrate that neuronal cannabinoid CB 1 receptors are synthesized in cells of the dorsal root ganglia and inserted on terminals in the periphery. ᭧ 1999 IBRO.

Objectives: Pain assessment is essential to tailor intensive care of neonates. The present focus is on acute procedural pain; assessment of pain of longer duration remains a challenge. We therefore tested a modified version of the... more

Objectives: Pain assessment is essential to tailor intensive care of neonates. The present focus is on acute procedural pain; assessment of pain of longer duration remains a challenge. We therefore tested a modified version of the COMFORT-behavior scale-named COMFORTneo-for its psychometric qualities in the Neonatal Intensive Care Unit setting.

The theory of myofascial pain syndrome (MPS) caused by trigger points (TrPs) seeks to explain the phenomena of muscle pain and tenderness in the absence of evidence for local nociception. Although it lacks external validity, many... more

The theory of myofascial pain syndrome (MPS) caused by trigger points (TrPs) seeks to explain the phenomena of muscle pain and tenderness in the absence of evidence for local nociception. Although it lacks external validity, many practitioners have uncritically accepted the diagnosis of MPS and its system of treatment. Furthermore, rheumatologists have implicated TrPs in the pathogenesis of chronic widespread pain (FM syndrome). We have critically examined the evidence for the existence of myofascial TrPs as putative pathological entities and for the vicious cycles that are said to maintain them. We find that both are inventions that have no scientific basis, whether from experimental approaches that interrogate the suspect tissue or empirical approaches that assess the outcome of treatments predicated on presumed pathology. Therefore, the theory of MPS caused by TrPs has been refuted. This is not to deny the existence of the clinical phenomena themselves, for which scientifically s...

Painful experience is a complex entity made up of sensory, affective, motivational and cognitive dimensions. The neural mechanisms involved in pain perception acts in a serial and a parallel way, discriminating and locating the original... more

Painful experience is a complex entity made up of sensory, affective, motivational and cognitive dimensions. The neural mechanisms involved in pain perception acts in a serial and a parallel way, discriminating and locating the original stimulus and also integrating the affective feeling, involved in a special situation, with previous memories. This review examines the concepts of nociception, acute and chronic pain, and also describes the afferent pathways involved in reception, segmental processing and encephalic projection of pain stimulus. The interaction model of the cerebral cortex areas and their functional characteristics are also discussed. D

Pain is a sensory experience and distinct from nociception, which refers to the neural mechanisms involved in detecting tissue damage. This article reviews nociceptive mechanisms and how these relate to pain sensation. The emphasis is on... more

Pain is a sensory experience and distinct from nociception, which refers to the neural mechanisms involved in detecting tissue damage. This article reviews nociceptive mechanisms and how these relate to pain sensation. The emphasis is on recent advances in our understanding of nociceptive mechanisms, including transduction at the peripheral nociceptor terminal, ascending pathways, and the cortical role in pain. Plasticity in nociceptive systems and a new role for descending systems in pain facilitation are also discussed.

Osteoarthritis is one of the most frequent, disabling, and costly pathologies of modern society. Among the main aims of osteoarthritis management are pain control and functional ability improvement. The exact cause of osteoarthritis pain... more

Osteoarthritis is one of the most frequent, disabling, and costly pathologies of modern society. Among the main aims of osteoarthritis management are pain control and functional ability improvement. The exact cause of osteoarthritis pain remains unclear. In addition to the pathological changes in articular structures, changes in central pain processing or central sensitization appear to be involved in osteoarthritis pain. The latter calls for a broader approach to the management of patients with osteoarthritis. Yet, the scientific literature offers scant information addressing the treatment of central sensitization, specifically in patients with osteoarthritis. Interventions such as cognitive-behavioral therapy and neuroscience education potentially target cognitive-emotional sensitization (and descending facilitation), and centrally acting drugs and exercise therapy can improve endogenous analgesia (descending inhibition) in patients with osteoarthritis. Future studies should assess these new treatment avenues.

Numerous approaches have been used to induce and measure experimental pain perception with the goal of better understanding excitatory and inhibitory pain mechanisms. In this study, the objective was to develop a simple experimental... more

Numerous approaches have been used to induce and measure experimental pain perception with the goal of better understanding excitatory and inhibitory pain mechanisms. In this study, the objective was to develop a simple experimental design which would enable us to elicit and measure multiple nociceptive mechanisms that have been reported to play a role in the development and persistency of chronic pain, such as temporal summation (TS) and diffuse noxious inhibitory control (DNIC). Eighty-three healthy subjects (42 men, 41 women) participated in this study where we examined pain perception of two tonic heat pain stimulation (thermode) separated by a 2 minute cold pressor test (CPT) (7°C, 10°C or 12°C) which allowed us to activate DNIC. The heat pain response was characterized by a peak pain during the first 30 s, which was stronger for women (p = 0.001). We also observed a TS phenomenon during the second minute of stimulation. DNIC's analgesia was assessed by measuring the difference in pain ratings between the two thermode procedures, before and after inducing DNIC by a cold pressure test on the opposite arm. We found that the mean pain ratings and peak pain but not TS were significantly reduced by DNIC. No sex differences were observed in DNIC analgesia.

Chronic pain is the most burdensome health issue facing the world today; its cost to Western countries is comparable with that of diabetes and cancer combined. Our understanding of the pathophysiology of chronic pain has increased... more

Chronic pain is the most burdensome health issue facing the world today; its cost to Western countries is comparable with that of diabetes and cancer combined. Our understanding of the pathophysiology of chronic pain has increased substantially over the past 20 years, including but not limited to changes in the brain. However, we still do not know why chronic pain develops in some people and not in others, although we do know that the type or extent of their injury, personality, occupation, postcode, education level, race, or religion are not strong predictors. 6 Extensive research into the genetics of chronic pain has also thus far been underwhelming, perhaps because too many genes are involved and results are conflicting. 12 Chronic pain is very difficult to treat; 60% of those with chronic pain will still be in pain after 1 year. 7 It seems that despite extensive advances in multiple fields, we have made little ground. In this topical review, we put forward a new hypothesis of chronic pain that explains the most common painful disorders, such as chronic widespread pain, nonspecific back or neck pain, and fibromyalgia. Our hypothesis draws on a long history of fundamental research in associative learning and is based on 2 core assumptions (1) that pain can be considered a response, not just a stimulus, and (2) that encoding nonnociceptive information predictably coincident with nociceptive input underpins the response to subsequent similar events. Briefly, our hypothesis posits that the precision with which multisensory information (temporal, proprioceptive, spatial) about the painful event is encoded and represented in the brain will determine the degree to which the painful response will subsequently generalize to similar events.

Sublethal injury triggers long-lasting sensitization of defensive responses in most species examined, suggesting the involvement of powerful evolutionary selection pressures . In humans, this persistent nociceptive sensitization is often... more

Sublethal injury triggers long-lasting sensitization of defensive responses in most species examined, suggesting the involvement of powerful evolutionary selection pressures . In humans, this persistent nociceptive sensitization is often accompanied by heightened sensations of pain and anxiety . While experimental and clinical [4] evidence support the adaptive value of immediate nociception during injury, no direct evidence exists for adaptive benefits of long-lasting sensitization after injury. Recently, we showed that minor injury produces long-term sensitization of behavioral and neuronal responses in squid, Doryteuthis pealei [5, 6]. Here we tested the adaptive value of this sensitization during encounters between squid and a natural fish predator. Locomotion and other spontaneous behaviors of squid that received distal injury to a single arm (with or without transient anesthesia) showed no measurable impairment 6 hr after the injury. However, black sea bass given access to freely swimming squid oriented toward and pursued injured squid at greater distances than uninjured squid, regardless of previous anesthetic treatment. Once targeted, injured squid began defensive behavioral sequences earlier than uninjured squid. This effect was blocked by brief anesthetic treatment that prevented development of nociceptive sensitization . Importantly, the early anesthetic treatment also reduced the subsequent escape and survival of injured, but not uninjured, squid. Thus, while minor injury increases the risk of predatory attack, it also triggers a sensitized state that promotes enhanced responsiveness to threats, increasing the survival (Darwinian fitness) of injured animals during subsequent predatory encounters.

Clinical research of graded exposure in vivo with behavioral experiments in patients with chronic low back pain who reported fear of movement/(re)injury shows abrupt changes in self-reported pain-related fears and cognitions. The abrupt... more

Clinical research of graded exposure in vivo with behavioral experiments in patients with chronic low back pain who reported fear of movement/(re)injury shows abrupt changes in self-reported pain-related fears and cognitions. The abrupt changes are more characteristics of insight learning rather than the usual gradual progression of trial and error learning. The educational session at the start of the exposure might have contributed to this insight. The current study examines the contribution of education and graded exposure versus graded activity in the reduction of pain-related fear and associated disability and physical activity. Six consecutive patients with chronic low back pain who reported substantial fear of movement/(re)injury were included in the study. After a no-treatment baseline measurement period, all the patients received a single educational session, followed again by a no-treatment period. Patients were then randomly assigned to either a graded exposure with behavioral experiments or an operant graded activity program. A diary was used to assess daily changes in pain intensity, pain-related fear, pain catastrophizing, and activity goal achievement. Standardized questionnaires of painrelated fear, pain vigilance, pain intensity, and pain disability were administered before and after each intervention and at the 6-month follow-up. An activity monitor was carried at baseline, during the interventions, and 1 week at 6-month follow-up. Randomization tests of the daily measures showed that improvements in pain-related fear and catastrophizing occurred after the education was introduced. The results also showed a further improvement when exposure in vivo followed the no-treatment period after the education and not during the operant graded activity program. Performance of relevant daily activities, however, were not affected by the educational session and improved significantly only in the exposure in vivo condition. All improvements remained at half-year follow-up only in patients receiving the exposure in vivo. These patients also reported a significant decrease in pain intensity at follow-up.

Laser-evoked potentials (LEPs) Nociception Posterior parietal cortex a b s t r a c t Introduction: Neuroimaging studies indicate that hypnotic suggestions of increased and decreased pain intensity and unpleasantness may modulate... more

Laser-evoked potentials (LEPs) Nociception Posterior parietal cortex a b s t r a c t Introduction: Neuroimaging studies indicate that hypnotic suggestions of increased and decreased pain intensity and unpleasantness may modulate somatosensory and cingulate cortex activity, respectively.

Differences in pain sensitivity between chronic pain patients and healthy controls have been reported. Seltzer and Seltzer extended this line of research in studying the sensitivity to non-painful stimuli. They reported that the 2-point... more

Differences in pain sensitivity between chronic pain patients and healthy controls have been reported. Seltzer and Seltzer extended this line of research in studying the sensitivity to non-painful stimuli. They reported that the 2-point discrimination threshold of chronic pain patients was higher than that of control subjects. However, the study of Seltzer and Seltzer suffered from several methodological shortcomings. Therefore, in the present study we tried to replicate the findings in a group of chronic low back pain patients using a design that was believed to be methodologically stronger. Replication failed: no evidence was found for the hypothesis that chronic pain patients are less sensitive to non-painful stimuli. Further studies on various defined types of acute and chronic pain patients are required.

Background: Monodora myristica (Gaertn) Dunal (Annonaceae) is used in traditional medicine for cough, rheumatism, hemorrhoids, diabetes, anemia and headaches. Objective: This study was carried out to investigate the antinociceptive and... more

Background: Monodora myristica (Gaertn) Dunal (Annonaceae) is used in traditional medicine for cough, rheumatism, hemorrhoids, diabetes, anemia and headaches. Objective: This study was carried out to investigate the antinociceptive and anti-inflammatory effects of the hydroethanolic seeds extract of Monodora myristca (HMM) in rodents. Methods: HMM (50-200 mg/kg, p.o.) was administered 1 h before intraperitoneal or intraplantar injection of V 0.6% /v acetic acid or 1% formalin (20 µL), respectively, to evaluate the antinociceptive property. Acute and chronic anti-inflammatory effect was investigated using carrageenan-induced paw and xylene-induced ear oedema, and cotton-pellet induced granuloma tests, respectively. Results: HMM (50-200 mg/kg) produced dose dependent and significant decrease in mean number of writhes in acetic acid-induced nociception and increased pain threshold to neurogenic and inflammatory pain with 48.59 and 34.2% inhibition, respectively, in the formalin-induced nociception assay. The HMM-induced antinociception was completely blocked by pre-treatment of mice with naloxone, p-Chlorophenyalanine (serotonin synthase inhibitor; 100 mg/kg, i.p.) and sulpiride (D receptor antagonist; 2 50mg/kg) whereas glibenclamide (K sensitive channels blocker; 10 mg/kg) failed to reverse the ATP antinociceptive effect of the extract. In acute inflammatory model, HMM produced time course inhibition of carrageenan-induced paw oedema. In addition, pretreatment of mice with HMM inhibited xylene-induced ear oedema by 60% comparatively similar to the effect of dexamethasone (83.90%). Moreover, in the cotton-pellet granuloma pouch, HMM (200 mg/kg) reduced granuloma formation by 52%. Conclusion: The hydro-ethanolic seed extract of M. myristica possesses antinociceptive effect mediated through interaction with opioidergic, serotonergic and dopaminergic systems and an anti-inflammatory action through inhibition of inflammatory mediator's release. Finally, the study established the scientific basis for its use in the management of pain and inflammatory conditions in traditional medicine.

Pain is the primary reason that people seek medical care. At present chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity,... more

Pain is the primary reason that people seek medical care. At present chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than two months duration and can be of an inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally nonnoxious stimuli), and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional pain drugs or surgical intervention and thus the study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on protein kinase C involvement in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as the master regulator of peripheral and central sensitization that underlies many chronic pain conditions.

Pain is a subjective experience that protects the body. This function implies a special relation between the brain mechanisms underlying pain perception and representation of the body. All sensory systems involve the body for the trivial... more

Pain is a subjective experience that protects the body. This function implies a special relation between the brain mechanisms underlying pain perception and representation of the body. All sensory systems involve the body for the trivial reason that sensory receptors are located in the body. The nociceptive system of detecting noxious stimuli comprises two classes of peripheral afferents, Aδ and C nociceptors, that cover almost the entire body surface. We review evidence from experimental studies of pain in humans and other animals suggesting that Aδ skin nociceptors project to a spatially-organised, somatotopic map in the primary somatosensory cortex. While the relation between pain perception and homeostatic regulation of bodily systems is widely acknowledged, the organization of nociceptive information into spatial maps of the body has received little attention. Importantly, the somatotopic neural organization of pain systems can shed light on pain-related plasticity and pain modulation. Finally, we show that the neural coding of noxious stimuli, and consequent experience of pain, are both strongly influenced when cognitive representations of the body are activated by viewing the body, as opposed to viewing another object - an effect we term 'visual analgesia'. We argue that pain perception involves some of the representational properties of exteroceptive senses, such as vision and touch. Pain, however, has the unique feature that the content of representation is the body itself, rather than any external object of perception. We end with some suggestions regarding how linking pain to body representation could shed light on clinical conditions, notably chronic pain.

Nerve growth factor (NGF) is central to the development and functional regulation of sensory neurons that signal the first events that lead to pain. These sensory neurons, called nociceptors, require NGF in the early embryo to survive and... more

Nerve growth factor (NGF) is central to the development and functional regulation of sensory neurons that signal the first events that lead to pain. These sensory neurons, called nociceptors, require NGF in the early embryo to survive and also for their functional maturation. The long road from the discovery of NGF and its roles during development to the realization that NGF plays a major role in the pathophysiology of inflammatory pain will be reviewed. In particular, we will discuss the various signaling events initiated by NGF that lead to long-lasting thermal and mechanical hyperalgesia in animals and in man. It has been realized relatively recently that humanized function blocking antibodies directed against NGF show remarkably analgesic potency in human clinical trials for painful conditions as varied as osteoarthritis, lower back pain, and interstitial cystitis. Thus, anti-NGF medication has the potential to make a major impact on day-to-day chronic pain treatment in the near...

Clinical research of graded exposure in vivo with behavioral experiments in patients with chronic low back pain who reported fear of movement/(re)injury shows abrupt changes in self-reported pain-related fears and cognitions. The abrupt... more

Clinical research of graded exposure in vivo with behavioral experiments in patients with chronic low back pain who reported fear of movement/(re)injury shows abrupt changes in self-reported pain-related fears and cognitions. The abrupt changes are more characteristics of insight learning rather than the usual gradual progression of trial and error learning. The educational session at the start of the exposure might have contributed to this insight. The current study examines the contribution of education and graded exposure versus graded activity in the reduction of pain-related fear and associated disability and physical activity. Six consecutive patients with chronic low back pain who reported substantial fear of movement/(re)injury were included in the study. After a no-treatment baseline measurement period, all the patients received a single educational session, followed again by a no-treatment period. Patients were then randomly assigned to either a graded exposure with behavioral experiments or an operant graded activity program. A diary was used to assess daily changes in pain intensity, pain-related fear, pain catastrophizing, and activity goal achievement. Standardized questionnaires of painrelated fear, pain vigilance, pain intensity, and pain disability were administered before and after each intervention and at the 6-month follow-up. An activity monitor was carried at baseline, during the interventions, and 1 week at 6-month follow-up. Randomization tests of the daily measures showed that improvements in pain-related fear and catastrophizing occurred after the education was introduced. The results also showed a further improvement when exposure in vivo followed the no-treatment period after the education and not during the operant graded activity program. Performance of relevant daily activities, however, were not affected by the educational session and improved significantly only in the exposure in vivo condition. All improvements remained at half-year follow-up only in patients receiving the exposure in vivo. These patients also reported a significant decrease in pain intensity at follow-up.

Context: Studies have shown that pomegranate, Punica granatum Linn. (Lythraceae), has remarkable biological and medicinal properties. Objective: This work aimed to explore and compare the analgesic and anti-inflammatory activities of the... more

Context: Studies have shown that pomegranate, Punica granatum Linn. (Lythraceae), has remarkable biological and
medicinal properties.
Objective: This work aimed to explore and compare the analgesic and anti-inflammatory activities of the methanol
extract (MoE) obtained from fruit peels of two varieties of pomegranate: Amrouz (MoEA) and Sefri (MoES).
Materials and methods: Antinociceptive activity of MoEA and MoES was examined using four models of pain. The
extracts were administered by the intraperitoneal route (i.p.) in writhing (50, 100 and 150 mg/kg) and formalin tests
(25, 50 and 100 mg/kg) and by intra-cerebroventricular injection (i.c.v.) in hotplate and tail-immersion tests (10, 25
and 50 µg/3 µl/rat). Anti-inflammatory activity was studied using the hind paw egg albumin test (50, 100 and 150 mg/
kg, i.p.).
Results: In the writhing test, the index of pain inhibition (IPI) was 52% for MoEA (150 mg/kg, i.p.) and 29% for MoES
(150 mg/kg, i.p.). In the formalin test, the IPI of early and late phase were, respectively, 75% and 82% for MoEA (100 mg/
kg, i.p.) and 8% and 63% for MoES (100 mg/kg, i.p.). In the hotplate and tail-immersion test, MoEA and MoES increased
in a dosedependent manner the reaction latency to the thermal stimuli. MoEA seems to be more potent than MoES.
Only the analgesic effect of MoEA was partially inhibited by pretreatment with naloxone. Both extracts exerted a
significant anti-inflammatory effect.
Discussion and conclusions: The results demonstrated that P. granatum contains active constituents, which possess
antinociceptive and anti-inflammatory activity, justifying its popular uses.
Keywords: Pomegranate fruit peel, methanol extract, intracerebroventricular injection, formalin test, opioid
system, egg albumin induced edema

Action editor Bradley Postle Published online xxx Keywords: Pain Attention Distraction Executive control Event-related potentials a b s t r a c t Because pain often signals the occurrence of potential tissue damage, nociceptive stimuli... more

Action editor Bradley Postle Published online xxx Keywords: Pain Attention Distraction Executive control Event-related potentials a b s t r a c t Because pain often signals the occurrence of potential tissue damage, nociceptive stimuli have the capacity to capture attention and interfere with ongoing cognitive activities.

Früh-und Neugeborene sind zwar nicht in der Lage,die von ihnen empfundenen Schmerzsensationen durch Sprache,dafür jedoch durch Gestik auszudrücken.Physischer Ausdruck der einschneidenden Auswirkungen von Schmerzen auf den gesamten... more

Früh-und Neugeborene sind zwar nicht in der Lage,die von ihnen empfundenen Schmerzsensationen durch Sprache,dafür jedoch durch Gestik auszudrücken.Physischer Ausdruck der einschneidenden Auswirkungen von Schmerzen auf den gesamten Organismus sind hormonelle,metabolische,immunologische und kardiovaskuläre Veränderungen.Neuere Untersuchungen unterstreichen die Bedeutung wiederholter nozizeptiver Einflüsse beim Neu-und Frühgeborenen auf die spätere psychophysiologische Entwicklung,hierbei kommt es zu einer verminderten Aufmerksamkeits-und Konzentrationsfähigkeit,einem gestörten Verhaltensmuster,einer gestörten Motorik,einer gesteigerten Irritabilität sowie einem gestörten Schlafund Essverhalten.Da vorangegangene wiederholte schmerzhafte Stimuli zu einer Sensitivierung sensorischer Afferenzen führen,unterstreicht dies die Forderung nach einer suffizienten Analgesie beim Neu-und Frühgeborenen.Um nozizeptive Reize in ausreichendem Maße zu blockieren,kommen bei einer Allgemeinanästhesie neben Lokalanästhetika vorzugsweise Opioide zum Einsatz.Bei ihrer Verwendung müssen jedoch sowohl die pharmakokinetischen als auch die pharmakodynamischen Unterschiede zum Erwachsenen beachtet werden.So haben Neu-und Frühgeborene: 1. Eine verminderte Leberenzymaktivität.Da diese für den Abbau und damit auch für die Elimination verantwortlich ist, kommt es in der Folge zu einer verlängerten Eliminationsrate mit länger als üblichen Wirkdauer, so dass Opioide nach operati-Opioidrezeptoren stellen wichtige Schaltstellen in der Funktion des zentralen Nervensystems, insbesondere in der Verarbeitung nozizeptiver Afferenzen dar. Ihre Bedeutung bei der Schmerzverarbeitung des Neu-und Frühgeborenen ist jedoch nur wenig untersucht worden. Viele Erkenntnisse zur Entwicklung und Funktion des Opioidsystems beim Menschen basieren auf Untersuchungsbefunden,die am Tier erhoben worden sind. Besonders aus den Entwicklungen im ZNS der Ratte, wird eine parallele Entwicklung beim Neu-und Frühgeborenen abgeleitet. So ist z.B.die vor allem in den ersten Lebenstagen ähnliche Reifung verschiedener Hirnareale,v.a.im Hirnstamm und im limbischen System,eine damit einhergehende ähnliche Verteilungsdichte von Opioidrezeptoren und eine dem Neugeborenen ähnliche Reaktion auf ein Opioid nachweisbar [66, 92]. Ein direkter Vergleich ist jedoch problematisch, denn während das Nervensystem einer neugeborenen Ratte dem eines 24 Wochen alten Feten entspricht, kommt das Nervensystem einer 7 Tage alten neugeborenen Ratte dem eines 3 Wochen alten Säuglings gleich. Somit erfährt das ZNS von Ratten eine im Vergleich zum ZNS des Menschen rasantere Entwicklung nach der Geburt, die schon nach 3-4 Wochen abgeschlossen ist [33]. Dennoch können einige der bei der Ratte beobachteten Ent-Kinderanästhesie Schmerz und Opioide bei Neugeborenen und Säuglingen © Springer-Verlag 2002 Prof. Dr. Enno Freye Deichstr.3A, 41468 Neuss-Uedesheim Redaktion R. Larsen, Homburg/Saar ven Eingriffen einen Überhang mit einer verlängerten Atemdepression aufweisen können. 2. Eine, besonders bei Frühgeborenen, noch nicht voll ausgebildete Blut-Hirn-Schranke.Es gelangt mehr freier Wirkstoff in das ZNS und zu den opioidspezifischen Bindestellen; eine Ausprägung der Nebenwirkungen insbesondere von Atemdepression, Bradykardie und Hypotension kann die Folge sein. 3. Ein Opioidrezeptorsystem, das noch nicht das endgültige Verhältnis von µ, δ und κ-Bindestellen aufweist.In Relation zum Körpergewicht können für eine suffiziente opioidbedingte Analgesie höhere Dosen notwendig werden. 4. Eine unterschiedlich schnelle Entwicklung von Opioidrezeptoren in den verschiedenen Arealen des schmerzverarbeitenden Nervensystems.Da im Bereich der Pons-Medulla-Region die Rezeptorenanzahl schneller als in den mehr rostral gelegenen Zentren zunimmt, ist eher mit einer Atemdepression, einer Bradykardie sowie einer muskulären Rigidität zu rechnen. Trotz dieser Besonderheiten stellen Opioide beim Früh-und Neugeborenen eine Gruppe von Analgetika dar, die für eine suffiziente Analgesie geeignet sind; die Dosierung sollte sich dabei aber nicht am Körpergewicht, sondern an der Wirkung orientieren. Schlüsselwörter Opioide · Opioidrezeptoren · Ontogenese · Früh-und Neugeborene · Antinozizeption · Langzeiteffekte Der Anaesthesist 4•2002 | 273 L. Latasch · E. Freye

Objectives: Research has provided us with an increased understanding of nociception-motor interaction. Nociception-motor interaction is most often processed without conscious thoughts. Hence, in many cases neither patients nor clinicians... more

Objectives: Research has provided us with an increased understanding of nociception-motor interaction. Nociception-motor interaction is most often processed without conscious thoughts. Hence, in many cases neither patients nor clinicians are aware of the interaction. It is aimed at reviewing the scientific literature on nociception-motor interaction, with emphasis on clinical implications.

This is the first study to examine, in the same sample, the effects of hypnosis, meditation, transcranial direct current stimulation (tDCS), and neurofeedback on pain and brain oscillations, relative to a control procedure. Each procedure... more

This is the first study to examine, in the same sample, the effects of hypnosis, meditation, transcranial direct current stimulation (tDCS), and neurofeedback on pain and brain oscillations, relative to a control procedure. Each procedure resulted in oscillation changes that differed from the control procedure and from each other, suggesting different modes of action on brain activity. Changes in pain intensity associated with the procedures were not, however, significantly associated with changes in brain oscillations, suggesting that brain activity measures used in this study do not reflect pain intensity.

A fucomannogalactan (FMG-Am) and a (1 → 3), (1 → 6)-linked ␤-d-glucan (␤GLC-Am) were isolated from Amanita muscaria fruiting bodies. These compounds' structures were determined using mono-and bidimensional NMR spectroscopy, methylation... more

A fucomannogalactan (FMG-Am) and a (1 → 3), (1 → 6)-linked ␤-d-glucan (␤GLC-Am) were isolated from Amanita muscaria fruiting bodies. These compounds' structures were determined using mono-and bidimensional NMR spectroscopy, methylation analysis, and controlled Smith degradation. FMG-Am was shown to be a heterogalactan formed by a (1 → 6)-linked ␣-d-galactopyranosyl main chain partially substituted at O-2 mainly by ␣-l-fucopyranose and a minor proportion of ␤-d-mannopyranose non-reducing end units. ␤GLC-Am was identified as a (1 → 3)-linked ␤-d-glucan partially substituted at O-6 by monoand a few oligosaccharide side chains, which was confirmed after controlled Smith degradation. Both the homo-and heteropolysaccharide were evaluated for their anti-inflammatory and antinociceptive potential, and they produced potent inhibition of inflammatory pain, specifically, 91 ± 8% (30 mg kg −1 ) and 88 ± 7% (10 mg kg −1 ), respectively.

Brain responses to pain, assessed through positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are reviewed. Functional activation of brain regions are thought to be reflected by increases in the regional... more

Brain responses to pain, assessed through positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are reviewed. Functional activation of brain regions are thought to be reflected by increases in the regional cerebral blood flow (rCBF) in PET studies, and in the blood oxygen level dependent (BOLD) signal in fMRI. rCBF increases to noxious stimuli are almost constantly observed in second somatic (SII) and insular regions, and in the anterior cingulate cortex (ACC), and with slightly less consistency in the contralateral thalamus and the primary somatic area (SI). Activation of the lateral thalamus, SI, SII and insula are thought to be related to the sensory-discriminative aspects of pain processing. SI is activated in roughly half of the studies, and the probability of obtaining SI activation appears related to the total amount of body surface stimulated (spatial summation) and probably also by temporal summation and attention to the stimulus. In a number of studies, the thalamic response was bilateral, probably reflecting generalised arousal in reaction to pain. ACC does not seem to be involved in coding stimulus intensity or location but appears to participate in both the affective and attentional concomitants of pain sensation, as well as in response selection. ACC subdivisions activated by painful stimuli partially overlap those activated in orienting and target detection tasks, but are distinct from those activated in tests involving sustained attention (Stroop, etc.). In addition to ACC, increased blood flow in the posterior parietal and prefrontal cortices is thought to reflect attentional and memory networks activated by noxious stimulation. Less noted but frequent activation concerns motor-related areas such as the striatum, cerebellum and supplementary motor area, as well as regions involved in pain control such as the periaqueductal grey. In patients, chronic spontaneous pain is associated with decreased resting rCBF in contralateral thalamus, which may be reverted by analgesic procedures. Abnormal pain evoked by innocuous stimuli (allodynia) has been associated with amplification of the thalamic, insular and SII responses, concomitant to a paradoxical CBF decrease in ACC. It is argued that imaging studies of allodynia should be encouraged in order to understand central reorganisations leading to abnormal cortical pain processing. A number of brain areas activated by acute pain, particularly the thalamus and anterior cingulate, also show increases in rCBF during analgesic procedures. Taken together, these data suggest that hemodynamic responses to pain reflect simultaneously the sensory, cognitive and affective dimensions of pain, and that the same structure may both respond to pain and participate in pain control. The precise biochemical nature of these mechanisms remains to be investigated.

The lateral capsular division (CeLC) of the central nucleus (Ce) of the amygdala, in the rat, has been shown to be the main terminal area of a spino(trigemino)-parabrachio-amygdaloid nociceptive pathway []. The projections to the... more

The lateral capsular division (CeLC) of the central nucleus (Ce) of the amygdala, in the rat, has been shown to be the main terminal area of a spino(trigemino)-parabrachio-amygdaloid nociceptive pathway []. The projections to the forebrain from the CeLC and adjacent regions were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L) restricted in subdivisions of the Ce and the basolateral amygdaloid nucleus anterior (BLA). Our data showed that the entire CeLC projects primarily and extensively to the substantia innominata dorsalis (SId). The terminal labelling is especially dense in the caudal aspect of the SId. The other projections of the CeLC in the forebrain were dramatically less dense. They terminate in the bed nucleus of the stria terminalis (BST) and the posterior hypothalamus (pLH). No (or only scarce) other projections were found in the remaining forebrain areas. The Ce lateral division (CeL) and the Ce medial division (CeM), adjacent to the CeLC, also project to the SId with slightly lower density labelling. However, contrary to the case of the CeLC, both the CeL and the CeM extensively project to the ventrolateral subnucleus of the BST (BSTvl) with a few additional terminals found in other regions of the lateral BST. Only the CeM projects densely to both the interstitial nucleus of the posterior limb of the anterior commissure and the caudal most portion of the pLH. The projections of the BLA are totally different from those of the Ce as they terminate in the dorsal striatum, the accumbens nucleus, the olfactory tubercle, the nucleus of olfactory tract and the rostral pole of the cingulate/frontal cortex. This study demonstrates that the major output of the nociceptive spino(trigemino)-parabrachio-CeLC pathway is to the SId. It is suggested that the CeLC±SId pathway could have an important role in anxiety, aversion and genesis of fear in response to noxious stimuli.

This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and... more

This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and opioid systems was investigated. It was evaluated if the administration of PCS triggers toxic effect. Treatment with PCS (10 mg/kg) reduced writhing induced by acetic acid and its effect lasts up to 48 h after treatment. The compound caused an inhibition in neurogenic and inflammatory phases of nociception and in paw edema induced by formalin. The licking behavior triggered by glutamate was reduced by PCS. In the tail-immersion test, PCS elicited an increase in delta latency response. Pretreatment with caffeine (3 mg/kg, intraperitoneally [i.p.]) and SCH58261 (3 mg/kg, i.p.), antagonist at adenosinergic receptors, SCH23390 (0.05 mg/kg, i.p.) and sulpiride (5 mg/kg, i.p.), antagonist at dopaminergic receptors, caused a reduction in the antinociceptive action of PCS in the glutamate test. By contrast, pretreatment with WAY100635 (0.7 mg/kg, i.p.), ketanserin (0.3 mg/kg, i.p.), ondasentron (0.5 mg/kg, i.p.), L-arginine (600 mg/kg, i.p.) and naloxone (1 mg/kg, subcutaneous [s.c.]) did not abolish the antinociceptive effect caused by PCS (10 mg/kg, i.g.) administration. The animals treated with PCS did not show alterations in locomotor and exploratory activities, in biochemical parameters evaluated, food and water consumption, as well as in the body weight. These results clearly showed the antinociceptive action of PCS in different animal models without causing acute toxic effects in mice. Adenosinergic and dopaminergic systems seem to be related to the mechanisms by which PCS elicits antinociception.

Background. Recovery from peripheral nerve repair is frequently incomplete. Hence drugs that enhance nerve regeneration are needed clinically. Objectives. To study the effects of nandrolone decanoate in a model of deficient reinnervation... more

Background. Recovery from peripheral nerve repair is frequently incomplete. Hence drugs that enhance nerve regeneration are needed clinically. Objectives. To study the effects of nandrolone decanoate in a model of deficient reinnervation in the rat. Methods. In 40 rats, a 40-mm segment of the left median nerve was removed and interposed between the stumps of a sectioned right median nerve. Starting 7 days after nerve grafting and continuing over a 6-month period, we administered nandrolone at a dose of 5 mg/kg/wk to half the rats (n = 20). All rats were assessed behaviorally for grasp function and nociceptive recovery for up to 6 months. At final assessment, reinnervated muscles were tested electrophysiologically and weighed. Results were compared between rats that had received versus not received nandrolone and versus 20 nongrafted controls. Results. Rats in the nandrolone group recovered finger flexion faster. At 90 days postsurgery, they had recovered 42% of normal grasp strength versus just 11% in rats grafted but not treated with nandrolone. At 180 days, the average values for grasp strength recovery in the nandrolone and no-nandrolone groups were 40% and 33% of normal values for controls, respectively. At 180 days, finger flexor muscle twitch strength was 16% higher in treated versus nontreated rats. Thresholds for nociception were not detected in either group 90 days after nerve grafting. At 180 days, nociceptive thresholds were significantly lower in the nandrolone group. Conclusions. Nandrolone decanoate improved functional recovery in a model of deficient reinnervation.

Cross-talk between the immune-and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)cells they may function as... more

Cross-talk between the immune-and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)cells they may function as important intermediate cells. This review summarizes the current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Our main focus is on mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation. Furthermore we discuss mechanisms involved in physical mast cell-nerve interactions. This article is part of a Special Issue entitled: Mast cells in inflammation. j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a d i s 2.1. Adhesion molecules in direct cell-cell contact

Metabotropic glutamate receptor 5 (mGlu5) has been suggested to play a role in the development and maintenance of chronic pain. mGlu5 is expressed at synapses throughout the pain neuraxis where it is believed to modulate the function of... more

Metabotropic glutamate receptor 5 (mGlu5) has been suggested to play a role in the development and maintenance of chronic pain. mGlu5 is expressed at synapses throughout the pain neuraxis where it is believed to modulate the function of ion channels that underlie nociceptive transduction and transmission. Injections of mGlu5 agonists cause hypersensitivity or nocifensive behavior when administered peripherally, intrathecally, and centrally. In addition, pharmacological antagonism of mGlu5 has been suggested to be analgesic in a variety of animal pain models. Unfortunately, the selectivity of antagonists used in these studies has been called into question, suggesting that at least some of the analgesic properties of putatively selective mGlu5 antagonists may be due to off-target effects. Despite a wealth of data supporting the targeting of mGlu5 to treat pain, both antagonist selectivity issues and the lack of an mGlu5 antagonist approved for use in humans have hindered testing beyond the preclinical stage.

Many neuropeptides involved in pain perception are generated by endoproteolytic cleavages of their precursor proteins by the proprotein convertases PC1 and PC2. To investigate the role of PC2 in nociception and analgesia, we tested... more

Many neuropeptides involved in pain perception are generated by endoproteolytic cleavages of their precursor proteins by the proprotein convertases PC1 and PC2. To investigate the role of PC2 in nociception and analgesia, we tested wild-type and PC2-null mice for their responses to mechanical and thermal nociceptive stimuli, before and after a short swim in cold or warm water. Basal responses and responses after a cold swim were similar between the two groups. However, after a short forced swim in warm water, PC2-null mice were significantly less responsive to the stimuli than wild-type mice, an indication of increased opioid-mediated stress-induced analgesia. The enhanced analgesia in PC2-null mice may be caused by an accumulation of opioid precursor processing intermediates with potent analgesic effects, or by loss of anti-opioid peptides.

Different effects upon the nociceptive response have been observed with exposure to acute and chronic stress in rats. In the present study we repeatedly submitted rats to restraint for 40 days, inducing hyperalgesia using the tail-flick... more

Different effects upon the nociceptive response have been observed with exposure to acute and chronic stress in rats. In the present study we repeatedly submitted rats to restraint for 40 days, inducing hyperalgesia using the tail-flick test. A new session of acute stress was applied at the end of 40 days period, and the chronically-stressed animals demonstrated analgesia after forced swimming, but not after restraint. The effect of stress interruption for 14 or 28 days on the nociceptive threshold was then investigated. The basal tail-flick latency remained decreased for at least 28 days (hyperalgesic effect). Following the periods of suspension, the animals were submitted to new session of acute restraint, and stress-induced analgesia was observed only after 28 days of stress interruption. Thus, the mechanisms involved in the long-lasting hyperalgesia presented in this study are not exactly the same as those responsible for the analgesia induced by acute stressors. After 40 days of chronic stress treatment, morphine was injected i.p. (1.0, 5.0 mg/kg or saline). The repeatedly stressed rats displayed decreased morphine effects on nociception compared to unstressed controls. The tolerance of the response to morphine agrees with previous studies suggesting that chronic restraint stress could modify the activity of opioid systems. #

Pharmacogenomics 9(2) future science group future science group * As given in respective publications (reference ID if available). ‡ Owing to the absence of nerve pathology on histological examination, commonly referred to as 'congenital... more

Pharmacogenomics 9(2) future science group future science group * As given in respective publications (reference ID if available). ‡ Owing to the absence of nerve pathology on histological examination, commonly referred to as 'congenital indifference to pain' (for a comprehensive review, see [18]). § To date, 37 different variations of the NTRK1 gene in families affected by CIPA are known (for a comprehensive review, see [43]). CIPA: Congenital insensitivity to pain with anhydrosis; FD: Familial dysautonomia; HSAN: Hereditary sensory and autonomic neuropathy; MIM#: Online Mendelian Inheritance in Man' database [201].