F. Pavone - Academia.edu (original) (raw)

Papers by F. Pavone

Research paper thumbnail of Effects of bremazocine on passive avoidance behaviour in mice

Archives internationales de pharmacodynamie et de thérapie, 1986

The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avo... more The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avoidance apparatus. In a first set of experiments, memory impairments following immediately posttraining bremazocine administration (0.025 and 0.05 but not 0.01 mg/kg), and memory improvements following immediately posttraining administration of the kappa-opioid-receptor antagonist MR-1452 (1.0 and 2.0 but not 0.5 mg/kg), were observed. No effect was evident when the drugs were injected starting 120 min after training. In a second set of experiments, the effects of bremazocine (0.05 mg/kg) were antagonized by a per se ineffective dose of MR-1452 (0.5 mg/kg), suggesting involvement of kappa-opioid-receptors. In a third set of experiments, the effects of bremazocine were enhanced by a per se ineffective (15 min) immobilization stress, and were decreased by familiarization with the passive avoidance apparatus. The results are discussed in terms of attenuation of emotionality following bremazo...

Research paper thumbnail of Effects of kappa-opioid receptor agonists on locomotor activity and memory processes in mice

Polish journal of pharmacology and pharmacy

The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomoto... more The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomotor activity (test: toggle-floor box) and memory (test: passive avoidance) were assessed in C57BL/6 (C57) and DB/2 (DBA) mice. The drugs administration resulted in activity depression in both strains, the effect was higher in DBA mice and was enhanced by pretreatment with haloperidol and with muscimol. Memory impairment was observed in DBA mice following posttraining administration of all drugs. This effect was enhanced by immobilization stress and decreased by familiarization with the apparatus. Memory improvement was evident in C57 mice (U-50,488 experiments). In a research carried out with CD1 mice, amygdaloid lesions decreased the memory impairing effect of U-50,488. The results are compared with those previously obtained with mu agonists and, as concerns memory, are discussed in terms of the involvement of emotional factors in mice responses to kappa agonists administration.

Research paper thumbnail of Length of social deprivation differently affects free-choice morphine consumption in C57BL/6J mice

Functional neurology

The effects of social deprivation on morphine consumption in C57BL/6J mice were investigated. Soc... more The effects of social deprivation on morphine consumption in C57BL/6J mice were investigated. Social or isolated animals (length of isolation: 7, 12, 17 days) were submitted to a free-choice between water and morphine hydrochloride solution (0.5 mg/ml). Isolation affects morphine consumption, with solitary housed mice drinking more morphine solution than socially housed animals. Moreover the amount of morphine intake depends on the duration of the isolation period to which mice are subjected. The importance of environmental factors on opiate consumption may be considered in terms of the possible implications of drug addiction in humans.

Research paper thumbnail of Naloxone-reversible effects of ethanol on passive avoidance behavior in mice

Physiological Psychology, 1983

Performance impairments were evident, in CD! mice tested in a passive avoidance apparatus, follow... more Performance impairments were evident, in CD! mice tested in a passive avoidance apparatus, following posttrial intraperitoneal administration of ethanol (1.0 and 2.0 glkg) or morphine (0.5 and 1.0 mglkg), or following posttrial immobilization stress (30 and 60 min). Lower doses of ethanol (0.5 glkg) or morphine (0.25 mglkg), or a shorter immobilization time (15 min) were ineffective. Ethanol, at an ineffective dose (0.50 glkg) enhanced both the effects of morphine and those of immobilization stress. The effects observed were antagonized by a per se ineffective dose of naloxone (1.0 mglkg). The possibility that opiates may have a critical but modulatory effect on the actions of ethanol and/or immobilization is discussed.

Research paper thumbnail of Reduction of oxotremorine-induced analgesia after chronic but not acute restraint stress

Psychopharmacology, 1991

The analgesic response (tail-flick latency) induced by the muscarinic cholinergic agonist oxotrem... more The analgesic response (tail-flick latency) induced by the muscarinic cholinergic agonist oxotremorine was investigated in DBA/2 mice exposed to acute (a single 2 h session) and chronic (2 h once daily for 10 days) restraint stress. While a single exposure to stress did not influence the antinociceptive effects of the cholinergic agonist, chronic stress induced a clear-cut reduction of the oxotremorine-induced analgesia. The results show an involvement of cholinergic mechanisms in the adaptive modulation of nociception after chronic stressful events.

Research paper thumbnail of Chronic administration of phosphatidylserine during ontogeny enhances subject-environment interactions and radial maze performance in C57BL/6 mice

Physiology & Behavior, 1990

A longitudinal behavioral study was performed in mice exposed to the bovine brain phospholipid ph... more A longitudinal behavioral study was performed in mice exposed to the bovine brain phospholipid phosphatidylserine (BC-PS) from birth until sixty days. Examination of treated and control pups revealed no effect of the treatment on body weight nor on sensorimotor reflexes. At one and two months of age, when placed in an open field and, particularly, in the presence of a novel object, treated mice were found more interactive with their environment than control mice. Finally, when submitted to a radial eight-arm maze problem, choice accuracy was higher and maze-running strategies more adaptive in treated than in control adult mice. These results suggest a stimulating effect of the treatment on subject-environment interactions during ontogeny underlying improved cognitive abilities in adulthood.

Research paper thumbnail of Morphine and Botulinum neurotoxin A: a successful pharmacological combination against pain?

Pharmacological Reports, 2011

Research paper thumbnail of The action of dopamine on rat caudate neurones intracellularly recorded

Neuroscience Letters, 1978

Research paper thumbnail of The effect of botulinum neurotoxin A on sciatic nerve injury-induced neuroimmunological changes in rat dorsal root ganglia and spinal cord

Neuroscience, 2011

Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP... more Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP-25) in nerve terminals to inhibit neuronal release and shows long-lasting antinociceptive action in neuropathic pain. However, its precise mechanism of action remains unclear. Our study aimed to characterize BoNT/A-induced neuroimmunological changes after chronic constriction injury (CCI) of the sciatic nerve. In the ipsilateral lumbar spinal cords of CCI-exposed rats, the mRNA of microglial marker (complement component 1q, C1q), astroglial marker (glial fibrillary acidic protein, GFAP), and prodynorphin were upregulated, as measured by reverse transcription-polymerase chain reaction (RT-PCR). No changes appeared in mRNA for proenkephalin, pronociceptin, or neuronal and inducible nitric oxide synthase (NOS1 and NOS2, respectively). In the dorsal root ganglia (DRG), an ipsilateral upregulation of prodynorphin, pronociceptin, C1q, GFAP, NOS1 and NOS2 mRNA and a downregulation of proenkephalin mRNA were observed. A single intraplantar BoNT/A (75 pg/paw) injection induced long-lasting antinociception in this model. BoNT/A diminished the injury-induced ipsilateral spinal upregulation of C1q mRNA. In the ipsilateral DRG a significant decrease of C1q-positive cell activation and of the upregulation of prodynorphin, pronociceptin and NOS1 mRNA was also observed following BoNT/A admistration. BoNT/A also diminished the injury-induced upregulation of SNAP-25 expression in both structures. We provide evidence that BoNT/A impedes injury-activated neuronal function in structures distant from the injection site, which is demonstrated by its influence on NOS1, prodynorphin and pronociceptin mRNA levels in the DRG. Moreover, the silence of microglia/macrophages after BoNT/A administration could be secondary to the inhibition of neuronal activity, but this decrease in neuroimmune interactions could be the key to the long-lasting BoNT/A effect on neuropathic pain.

Research paper thumbnail of Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models

Neuroscience, 2010

A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) fo... more A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve both in mice and in rats. This effect is already present after a single intraplantar (i.pl.) or intrathecal (i.t.) neurotoxin administration that significantly reduces the sciatic nerve ligation-induced mechanical allodynia in mice and rats and thermal hyperalgesia in rats. This effect was evident starting 24 h after the administration of BoNT/A and it was long-lasting, being present 81 or 25 days after i.pl. injection of the higher dose in mice (15 pg/paw) and rats (75 pg/paw), respectively, and 35 days after i.t. injection in rats (75 pg/rat). Moreover, BoNT/A-injected mice showed a quicker recovery of the walking pattern and weight bearing compared to control groups. The behavioral improvement was accompanied by structural modifications, as revealed by the expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve, and by the immunofluorescence expression of S100␤ and glial fibrillary acidic protein (GFAP) Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and immunohistochemistry/blotting analysis. These results may have important implications in the therapy of neuropathic pain.

Research paper thumbnail of The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models

Journal of Pharmacology and Experimental Therapeutics, 2012

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a nove... more The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; Narachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and Npalmitoylethanolamine (PEA), were measured in control and ST4070treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor ␣ antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl-]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl-]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain. Sigma-Tau S.p.A. supported this work and may have financial interest to further develop the compound investigated. A.C.

Research paper thumbnail of 925 Comparison Between Short- and Long-Lasting Treadmill Exercise: Effects on Mechanical Allodynia and Functional Recovery After Sciatic Nerve Injury

European Journal of Pain, 2009

Backgrounds and Aims: To our knowledge, quantification of palpation pressures used by experienced... more Backgrounds and Aims: To our knowledge, quantification of palpation pressures used by experienced practitioners of osteopathy in the cranial field has not been reported to date. The objective of this study was to evaluate the pressure of palpation used by professional osteopaths during a cranial test procedure, and to determine the relationship between palpation pressures and years of practice (yop) experience. Methods: 43 participants (32 men and 11 women; aged 25–65 years) were enrolled after written consent was obtained. Data on palpation pressures employed during the study were obtained using a FlexiForce tactile force sensor device which recorded a 3-seconds pressure measurement. Practitioners’ yop and percentage of daily practice employing osteopathic cranial treatment were also recorded. Results: The palpation pressures recorded throughout the study procedure ranged from 0 to 1.81N/cm, with the mean pressure of the 3-seconds tests ranging from 0.01 to 1.69N/cm. Comparison among treatment groups was carried out using non-parametric analysis of variance with the Kruskall-Wallis test, followed by Dunn’s test for multiple group comparisons. The results suggested that practitioners with >20 yop use significantly less pressure than practitioners with less than 20 yop (p =0.024). Conclusions: This study is the first to provide data on the palpation pressures used during osteopathic cranial treatment. The results suggest that the application of cranial palpation is extremely variable. Highly experienced practitioners may use less pressure and demonstrate less variation; however, a significant proportion of less experienced practitioners use comparable pressure.

Research paper thumbnail of 141 Botulinum Neurotoxins: New Frontiers in Neuropathic Pain Therapy?

European Journal of Pain, 2007

Chronic post-ischemia pain (CPIP) is an animal model of CRPS-I produced by prolonged (3 h) I-R Po... more Chronic post-ischemia pain (CPIP) is an animal model of CRPS-I produced by prolonged (3 h) I-R Poster Presentations / Animal Models / European Journal of Pain 11(S1) (2007) S59-S207 S61

Research paper thumbnail of In vitro receptor binding properties of a “painless” NGF mutein, linked to hereditary sensory autonomic neuropathy type V

Biochemical and Biophysical Research Communications, 2010

Nerve Growth Factor (NGF) signalling is mediated by the TrkA and p75NTR receptors. Besides its ne... more Nerve Growth Factor (NGF) signalling is mediated by the TrkA and p75NTR receptors. Besides its neurotrophic and survival activities, NGF displays a potent pro-nociceptive activity. Recently, a missense point mutation was found in the NGFB gene (C661T, leading to the aminoacid substitution R100W) of individuals affected by a form of hereditary loss of pain perception (hereditary sensory and autonomic neuropathy type V, HSAN V). In order to gain insights into the functional consequences of the HSAN V NGF mutation, two sets of hNGFR100 mutants were expressed in Escherichia coli and purified, as mature NGF or proNGF, for in vitro receptor binding studies. Here, we show by Surface Plasmon Resonance analysis that the R100 mutation selectively disrupts binding of hNGF to p75NTR receptor, to an extent which depends on the substituting residue at position 100, while the affinity of hNGFR100 mutants for TrkA receptor is not affected. As for unprocessed hproNGF, the binding of the R100 variants to p75NTR receptor shows only a limited impairment, showing that the impact of the R100 mutation on p75NTR receptor binding is greater in the context of mature, processed hNGF. These results provide a basis for elucidating the mechanisms underlying the clinical manifestations of HSAN V patients, and provide a basis for the development of ''painless" hNGF molecules with therapeutic potential.

Research paper thumbnail of Effects of flunitrazepam on passive avoidance behaviour in mice subjected to immobilization stress or familiarized with the testing apparatus

Behavioural Brain Research, 1986

The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a... more The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a first set of experiments retention performance impairment was observed in mice injected with the drug immediately but not 120 min after training. In a second set of experiments, immobilization stress enhanced, while familiarization with the apparatus decreased, the effects of flunitrazepam, suggesting involvement of emotional factors. All the effects observed were antagonized by naltrexone, showing involvement of opioid receptors.

Research paper thumbnail of Memory modulation by stress in morphine or ethanol injected mice

Research paper thumbnail of CNF1 Bacterial Toxin Protein from E. Coli as Analgesic

Research paper thumbnail of Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice

Brain, Behavior, and Immunity, 2012

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin se... more Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.

Research paper thumbnail of P298 Treadmill Exercise Counteracts Neuropathic Pain and Stimulates Functional Recovery After Nerve Injury

Treadmill locomotion is widely used for physical rehabilitative therapy. Although several studies... more Treadmill locomotion is widely used for physical rehabilitative therapy. Although several studies demonstrate the positive effects of treadmill running on the functional recovery after a nerve injury, the effects on pain symptoms has not been investigated. In this study we analyzed which treadmill protocol could be effective both on functional recovery and on alleviation of neuropathic pain symptoms. Chronic Constriction Injury (CCI) model was used to induce neuropathy in mice. We measured the onset of mechanical allodynia in mice undergoing short(1 week) or long-lasting (8 weeks) daily sessions of treadmill exercise. Functional recovery of the injured paw was examined by analyzing weight bearing of hind limb, walking track analysis and Sciatic Static Index. Behavioural data were correlated with data deriving from immunofluorescence staining for markers of cellular proliferation (Cdc2, GAP-43) in injured nerves and of activated glial cells (Cd11b, GFAP) in lumbar spinal cord. An ear...

Research paper thumbnail of Opioid benzodiazepine tifluadom and drug-induced hyperactivity in mice: lack of benzodiazepine-like effects

Polish journal of pharmacology and pharmacy

The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compare... more The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compared for their influence on morphine and scopolamine-induced locomotor stimulation in mice. Diazepam enhanced drug-induced hyperactivity, while tifluadom had no effect or reduced locomotor activity. The results demonstrate that tifluadom, a benzodiazepine compound possessing opiate-like analgesic properties, is devoid of either benzodiazepine or morphine-like effects in activity tests.

Research paper thumbnail of Effects of bremazocine on passive avoidance behaviour in mice

Archives internationales de pharmacodynamie et de thérapie, 1986

The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avo... more The effects of bremazocine on memory processes were studied in DBA/2 mice tested in a passive avoidance apparatus. In a first set of experiments, memory impairments following immediately posttraining bremazocine administration (0.025 and 0.05 but not 0.01 mg/kg), and memory improvements following immediately posttraining administration of the kappa-opioid-receptor antagonist MR-1452 (1.0 and 2.0 but not 0.5 mg/kg), were observed. No effect was evident when the drugs were injected starting 120 min after training. In a second set of experiments, the effects of bremazocine (0.05 mg/kg) were antagonized by a per se ineffective dose of MR-1452 (0.5 mg/kg), suggesting involvement of kappa-opioid-receptors. In a third set of experiments, the effects of bremazocine were enhanced by a per se ineffective (15 min) immobilization stress, and were decreased by familiarization with the passive avoidance apparatus. The results are discussed in terms of attenuation of emotionality following bremazo...

Research paper thumbnail of Effects of kappa-opioid receptor agonists on locomotor activity and memory processes in mice

Polish journal of pharmacology and pharmacy

The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomoto... more The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomotor activity (test: toggle-floor box) and memory (test: passive avoidance) were assessed in C57BL/6 (C57) and DB/2 (DBA) mice. The drugs administration resulted in activity depression in both strains, the effect was higher in DBA mice and was enhanced by pretreatment with haloperidol and with muscimol. Memory impairment was observed in DBA mice following posttraining administration of all drugs. This effect was enhanced by immobilization stress and decreased by familiarization with the apparatus. Memory improvement was evident in C57 mice (U-50,488 experiments). In a research carried out with CD1 mice, amygdaloid lesions decreased the memory impairing effect of U-50,488. The results are compared with those previously obtained with mu agonists and, as concerns memory, are discussed in terms of the involvement of emotional factors in mice responses to kappa agonists administration.

Research paper thumbnail of Length of social deprivation differently affects free-choice morphine consumption in C57BL/6J mice

Functional neurology

The effects of social deprivation on morphine consumption in C57BL/6J mice were investigated. Soc... more The effects of social deprivation on morphine consumption in C57BL/6J mice were investigated. Social or isolated animals (length of isolation: 7, 12, 17 days) were submitted to a free-choice between water and morphine hydrochloride solution (0.5 mg/ml). Isolation affects morphine consumption, with solitary housed mice drinking more morphine solution than socially housed animals. Moreover the amount of morphine intake depends on the duration of the isolation period to which mice are subjected. The importance of environmental factors on opiate consumption may be considered in terms of the possible implications of drug addiction in humans.

Research paper thumbnail of Naloxone-reversible effects of ethanol on passive avoidance behavior in mice

Physiological Psychology, 1983

Performance impairments were evident, in CD! mice tested in a passive avoidance apparatus, follow... more Performance impairments were evident, in CD! mice tested in a passive avoidance apparatus, following posttrial intraperitoneal administration of ethanol (1.0 and 2.0 glkg) or morphine (0.5 and 1.0 mglkg), or following posttrial immobilization stress (30 and 60 min). Lower doses of ethanol (0.5 glkg) or morphine (0.25 mglkg), or a shorter immobilization time (15 min) were ineffective. Ethanol, at an ineffective dose (0.50 glkg) enhanced both the effects of morphine and those of immobilization stress. The effects observed were antagonized by a per se ineffective dose of naloxone (1.0 mglkg). The possibility that opiates may have a critical but modulatory effect on the actions of ethanol and/or immobilization is discussed.

Research paper thumbnail of Reduction of oxotremorine-induced analgesia after chronic but not acute restraint stress

Psychopharmacology, 1991

The analgesic response (tail-flick latency) induced by the muscarinic cholinergic agonist oxotrem... more The analgesic response (tail-flick latency) induced by the muscarinic cholinergic agonist oxotremorine was investigated in DBA/2 mice exposed to acute (a single 2 h session) and chronic (2 h once daily for 10 days) restraint stress. While a single exposure to stress did not influence the antinociceptive effects of the cholinergic agonist, chronic stress induced a clear-cut reduction of the oxotremorine-induced analgesia. The results show an involvement of cholinergic mechanisms in the adaptive modulation of nociception after chronic stressful events.

Research paper thumbnail of Chronic administration of phosphatidylserine during ontogeny enhances subject-environment interactions and radial maze performance in C57BL/6 mice

Physiology & Behavior, 1990

A longitudinal behavioral study was performed in mice exposed to the bovine brain phospholipid ph... more A longitudinal behavioral study was performed in mice exposed to the bovine brain phospholipid phosphatidylserine (BC-PS) from birth until sixty days. Examination of treated and control pups revealed no effect of the treatment on body weight nor on sensorimotor reflexes. At one and two months of age, when placed in an open field and, particularly, in the presence of a novel object, treated mice were found more interactive with their environment than control mice. Finally, when submitted to a radial eight-arm maze problem, choice accuracy was higher and maze-running strategies more adaptive in treated than in control adult mice. These results suggest a stimulating effect of the treatment on subject-environment interactions during ontogeny underlying improved cognitive abilities in adulthood.

Research paper thumbnail of Morphine and Botulinum neurotoxin A: a successful pharmacological combination against pain?

Pharmacological Reports, 2011

Research paper thumbnail of The action of dopamine on rat caudate neurones intracellularly recorded

Neuroscience Letters, 1978

Research paper thumbnail of The effect of botulinum neurotoxin A on sciatic nerve injury-induced neuroimmunological changes in rat dorsal root ganglia and spinal cord

Neuroscience, 2011

Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP... more Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP-25) in nerve terminals to inhibit neuronal release and shows long-lasting antinociceptive action in neuropathic pain. However, its precise mechanism of action remains unclear. Our study aimed to characterize BoNT/A-induced neuroimmunological changes after chronic constriction injury (CCI) of the sciatic nerve. In the ipsilateral lumbar spinal cords of CCI-exposed rats, the mRNA of microglial marker (complement component 1q, C1q), astroglial marker (glial fibrillary acidic protein, GFAP), and prodynorphin were upregulated, as measured by reverse transcription-polymerase chain reaction (RT-PCR). No changes appeared in mRNA for proenkephalin, pronociceptin, or neuronal and inducible nitric oxide synthase (NOS1 and NOS2, respectively). In the dorsal root ganglia (DRG), an ipsilateral upregulation of prodynorphin, pronociceptin, C1q, GFAP, NOS1 and NOS2 mRNA and a downregulation of proenkephalin mRNA were observed. A single intraplantar BoNT/A (75 pg/paw) injection induced long-lasting antinociception in this model. BoNT/A diminished the injury-induced ipsilateral spinal upregulation of C1q mRNA. In the ipsilateral DRG a significant decrease of C1q-positive cell activation and of the upregulation of prodynorphin, pronociceptin and NOS1 mRNA was also observed following BoNT/A admistration. BoNT/A also diminished the injury-induced upregulation of SNAP-25 expression in both structures. We provide evidence that BoNT/A impedes injury-activated neuronal function in structures distant from the injection site, which is demonstrated by its influence on NOS1, prodynorphin and pronociceptin mRNA levels in the DRG. Moreover, the silence of microglia/macrophages after BoNT/A administration could be secondary to the inhibition of neuronal activity, but this decrease in neuroimmune interactions could be the key to the long-lasting BoNT/A effect on neuropathic pain.

Research paper thumbnail of Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models

Neuroscience, 2010

A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) fo... more A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve both in mice and in rats. This effect is already present after a single intraplantar (i.pl.) or intrathecal (i.t.) neurotoxin administration that significantly reduces the sciatic nerve ligation-induced mechanical allodynia in mice and rats and thermal hyperalgesia in rats. This effect was evident starting 24 h after the administration of BoNT/A and it was long-lasting, being present 81 or 25 days after i.pl. injection of the higher dose in mice (15 pg/paw) and rats (75 pg/paw), respectively, and 35 days after i.t. injection in rats (75 pg/rat). Moreover, BoNT/A-injected mice showed a quicker recovery of the walking pattern and weight bearing compared to control groups. The behavioral improvement was accompanied by structural modifications, as revealed by the expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve, and by the immunofluorescence expression of S100␤ and glial fibrillary acidic protein (GFAP) Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and immunohistochemistry/blotting analysis. These results may have important implications in the therapy of neuropathic pain.

Research paper thumbnail of The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models

Journal of Pharmacology and Experimental Therapeutics, 2012

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a nove... more The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; Narachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and Npalmitoylethanolamine (PEA), were measured in control and ST4070treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor ␣ antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl-]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl-]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain. Sigma-Tau S.p.A. supported this work and may have financial interest to further develop the compound investigated. A.C.

Research paper thumbnail of 925 Comparison Between Short- and Long-Lasting Treadmill Exercise: Effects on Mechanical Allodynia and Functional Recovery After Sciatic Nerve Injury

European Journal of Pain, 2009

Backgrounds and Aims: To our knowledge, quantification of palpation pressures used by experienced... more Backgrounds and Aims: To our knowledge, quantification of palpation pressures used by experienced practitioners of osteopathy in the cranial field has not been reported to date. The objective of this study was to evaluate the pressure of palpation used by professional osteopaths during a cranial test procedure, and to determine the relationship between palpation pressures and years of practice (yop) experience. Methods: 43 participants (32 men and 11 women; aged 25–65 years) were enrolled after written consent was obtained. Data on palpation pressures employed during the study were obtained using a FlexiForce tactile force sensor device which recorded a 3-seconds pressure measurement. Practitioners’ yop and percentage of daily practice employing osteopathic cranial treatment were also recorded. Results: The palpation pressures recorded throughout the study procedure ranged from 0 to 1.81N/cm, with the mean pressure of the 3-seconds tests ranging from 0.01 to 1.69N/cm. Comparison among treatment groups was carried out using non-parametric analysis of variance with the Kruskall-Wallis test, followed by Dunn’s test for multiple group comparisons. The results suggested that practitioners with >20 yop use significantly less pressure than practitioners with less than 20 yop (p =0.024). Conclusions: This study is the first to provide data on the palpation pressures used during osteopathic cranial treatment. The results suggest that the application of cranial palpation is extremely variable. Highly experienced practitioners may use less pressure and demonstrate less variation; however, a significant proportion of less experienced practitioners use comparable pressure.

Research paper thumbnail of 141 Botulinum Neurotoxins: New Frontiers in Neuropathic Pain Therapy?

European Journal of Pain, 2007

Chronic post-ischemia pain (CPIP) is an animal model of CRPS-I produced by prolonged (3 h) I-R Po... more Chronic post-ischemia pain (CPIP) is an animal model of CRPS-I produced by prolonged (3 h) I-R Poster Presentations / Animal Models / European Journal of Pain 11(S1) (2007) S59-S207 S61

Research paper thumbnail of In vitro receptor binding properties of a “painless” NGF mutein, linked to hereditary sensory autonomic neuropathy type V

Biochemical and Biophysical Research Communications, 2010

Nerve Growth Factor (NGF) signalling is mediated by the TrkA and p75NTR receptors. Besides its ne... more Nerve Growth Factor (NGF) signalling is mediated by the TrkA and p75NTR receptors. Besides its neurotrophic and survival activities, NGF displays a potent pro-nociceptive activity. Recently, a missense point mutation was found in the NGFB gene (C661T, leading to the aminoacid substitution R100W) of individuals affected by a form of hereditary loss of pain perception (hereditary sensory and autonomic neuropathy type V, HSAN V). In order to gain insights into the functional consequences of the HSAN V NGF mutation, two sets of hNGFR100 mutants were expressed in Escherichia coli and purified, as mature NGF or proNGF, for in vitro receptor binding studies. Here, we show by Surface Plasmon Resonance analysis that the R100 mutation selectively disrupts binding of hNGF to p75NTR receptor, to an extent which depends on the substituting residue at position 100, while the affinity of hNGFR100 mutants for TrkA receptor is not affected. As for unprocessed hproNGF, the binding of the R100 variants to p75NTR receptor shows only a limited impairment, showing that the impact of the R100 mutation on p75NTR receptor binding is greater in the context of mature, processed hNGF. These results provide a basis for elucidating the mechanisms underlying the clinical manifestations of HSAN V patients, and provide a basis for the development of ''painless" hNGF molecules with therapeutic potential.

Research paper thumbnail of Effects of flunitrazepam on passive avoidance behaviour in mice subjected to immobilization stress or familiarized with the testing apparatus

Behavioural Brain Research, 1986

The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a... more The effects of flunitrazepam on passive avoidance behaviour were investigated in DBA/2 mice. In a first set of experiments retention performance impairment was observed in mice injected with the drug immediately but not 120 min after training. In a second set of experiments, immobilization stress enhanced, while familiarization with the apparatus decreased, the effects of flunitrazepam, suggesting involvement of emotional factors. All the effects observed were antagonized by naltrexone, showing involvement of opioid receptors.

Research paper thumbnail of Memory modulation by stress in morphine or ethanol injected mice

Research paper thumbnail of CNF1 Bacterial Toxin Protein from E. Coli as Analgesic

Research paper thumbnail of Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice

Brain, Behavior, and Immunity, 2012

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin se... more Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.

Research paper thumbnail of P298 Treadmill Exercise Counteracts Neuropathic Pain and Stimulates Functional Recovery After Nerve Injury

Treadmill locomotion is widely used for physical rehabilitative therapy. Although several studies... more Treadmill locomotion is widely used for physical rehabilitative therapy. Although several studies demonstrate the positive effects of treadmill running on the functional recovery after a nerve injury, the effects on pain symptoms has not been investigated. In this study we analyzed which treadmill protocol could be effective both on functional recovery and on alleviation of neuropathic pain symptoms. Chronic Constriction Injury (CCI) model was used to induce neuropathy in mice. We measured the onset of mechanical allodynia in mice undergoing short(1 week) or long-lasting (8 weeks) daily sessions of treadmill exercise. Functional recovery of the injured paw was examined by analyzing weight bearing of hind limb, walking track analysis and Sciatic Static Index. Behavioural data were correlated with data deriving from immunofluorescence staining for markers of cellular proliferation (Cdc2, GAP-43) in injured nerves and of activated glial cells (Cd11b, GFAP) in lumbar spinal cord. An ear...

Research paper thumbnail of Opioid benzodiazepine tifluadom and drug-induced hyperactivity in mice: lack of benzodiazepine-like effects

Polish journal of pharmacology and pharmacy

The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compare... more The opioid benzodiazepine, tifluadom, and the benzodiazepine tranquilizer, diazepam, were compared for their influence on morphine and scopolamine-induced locomotor stimulation in mice. Diazepam enhanced drug-induced hyperactivity, while tifluadom had no effect or reduced locomotor activity. The results demonstrate that tifluadom, a benzodiazepine compound possessing opiate-like analgesic properties, is devoid of either benzodiazepine or morphine-like effects in activity tests.