Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain (original) (raw)
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Opioids in neuropathic pain: clues from animal studies
European Journal of Pain, 2005
For many years the clinical consensus was that opioids were ineffective in neuropathic pain. However this view is changing and here we discuss the mechanisms of opioid analgesia in terms of the changes that can occur in preclinical models of nerve injury. We argue that opioid mechanisms can be perturbed by neuropathy but in most cases these negative influences can be overcome by doseescalation.
Pharmacotherapy for neuropathic pain: progress and prospects
Drug news & perspectives, 2003
Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral pain signaling pathway, has become an area of intense research activity--largely because it represents a disorder with high unmet medical need. It is not a single disease entity, but rather includes a range of heterogeneous conditions that differ in etiology, location and initiating cause. Despite this diversity, the clinical presentation is frequently surprisingly similar, which suggests a common biological basis. Until recently, little was known of the mechanisms underlying the various neuropathic pain conditions, making the directed development of novel therapies almost impossible. However, the steady increase in our understanding of the anatomical, cellular and molecular basis of neuropathic pain, coupled with the advent of a number of experimental models of neuropathy, has permitted relatively rapid progress, and the prospects for the emergence of new, more effective therapies look ve...
Pharmacological Management of Neuropathic Pain: Current Trends and Possible Approaches
Archives of Neuroscience, 2016
Context: Neuropathic pain (NP) is a chronic debilitating painful condition with complex pathophysiology and inadequate treatment. Conventional pharmacological approaches and currently available drugs only provide marginal pain relief and cause significant adverse effects. The present manuscript is an attempt to summarize the existing data and possible pharmacological approaches available for NP. Evidence Acquisition: Information was collected from Google Scholar, Cochrane and PubMed databases, Scopus and directory of open access journals. Neuropathic pain, chronic pain, diabetic neuropathy, pathophysiology and current recommendations were the terms used to search the literature. Data from relevant animal and randomized controlled studies were selected to get the up to date information of the currently available pharmacological approaches. A note on future approaches was added based on the recent animal and human studies. Results: The current review made a significant attempt to focus on the mode of action, required dosage, advantages and the side effect profiles of currently available drugs used, or investigational phases and their possible combinations to manage NP. Efforts are made to cover arise of NP because of diabetes and its management. At the end, authors made an attempt to cover the various therapeutic options that are currently explored for future drug development. Conclusions: The available pharmacological approaches are effective on one or other types of chronic pain. But the inadequate pain relief and limitations with each class of drugs raises the need to develop better therapeutic approaches and also understand the pathology better. The present review may be helpful to researchers intending to focus on newer therapeutic strategies and targets to manage NP.
Novel Therapies for the Treatment of Neuropathic Pain: Potential and Pitfalls
Journal of Clinical Medicine
Neuropathic pain affects more than one million people across the globe. The quality of life of people suffering from neuropathic pain has been considerably declining due to the unavailability of appropriate therapeutics. Currently, available treatment options can only treat patients symptomatically, but they are associated with severe adverse side effects and the development of tolerance over prolonged use. In the past decade, researchers were able to gain a better understanding of the mechanisms involved in neuropathic pain; thus, continuous efforts are evident, aiming to develop novel interventions with better efficacy instead of symptomatic treatment. The current review discusses the latest interventional strategies used in the treatment and management of neuropathic pain. This review also provides insights into the present scenario of pain research, particularly various interventional techniques such as spinal cord stimulation, steroid injection, neural blockade, transcranial/ep...
Frontiers in Cellular Neuroscience
Opioids play a major role at descending pain modulation but the effects of neuropathic pain on the brain opioidergic system remain understudied. Since descending facilitation is enhanced during neuropathic pain, we studied the opioidergic modulation of the dorsal reticular nucleus (DRt), a medullary pain facilitatory area, in the spared nerve injury (SNI) model of neuropathic pain. We first performed a series of behavioral experiments in naïve-animals to establish the role of µ-opioid receptor (MOR) in the effects of endogenous and exogenous opioids at the DRt. Specifically, we showed that lentiviral-mediated MOR-knockdown at the DRt increased sensitivity to thermal and mechanical stimuli while the MOR agonist DAMGO induced the opposite effects. Additionally, we showed that MOR-knockdown and the pharmacological blockade of MOR by CTAP at the DRt decreased and inhibited, respectively, the analgesic effects of systemic morphine. Then, we performed in vivo microdialysis to measure enkephalin peptides in the DRt and evaluated MOR expression in the DRt at mRNA, protein and phosphorylated form levels by quantitative real-time PCR and immunohistochemistry, respectively. SNI-animals, compared to sham control, showed higher levels of enkephalin peptides, lower MOR-labeled cells without alterations in MOR mRNA levels, and higher phosphorylated MOR-labeled cells. Finally, we performed behavioral studies in SNI animals to determine the potency of systemic morphine and the effects of the pharmacologic and genetic manipulation of MOR at the DRt. We showed a reduced potency of the antiallodynic effects of systemic morphine in SNI-animals compared to the antinociceptive effects in sham animals. Increasing MOR-cells at the DRt of SNI-animals by lentiviral-mediated MOR-overexpression produced no effects on mechanical allodynia. DAMGO induced anti-allodynia only after MOR-overexpression. These results show that MOR inhibits DRt pain facilitatory actions and that this action contributes to the analgesic effects of systemic opioids. We further show that the inhibitory function of MOR is impaired during neuropathic pain. This is
Anesthesiology, 2001
Background Tetrodotoxin-resistant Na(+) channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na(+) channel--blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia. Methods Tetrodotoxin-resistant Na(+) currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration-inhibition curves at different holding potentials (-90, -...
Recent advances in pharmacological treatment of neuropathic pain
F1000 Medicine Reports, 2010
Recent studies investigating the pharmacological management of neuropathic pain support the efficacy of certain antidepressants, anticonvulsants, and opioids. Novel directions in drug applications include topical applications of patches with either lidocaine or capsaicin and intradermal injections of botulinum toxin. In cases of partial pain relief, drug combinations may be considered.
Neuropathic pain treatment: still a challenge
Neuropathic pain (NP) is the result of a series of conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of NP pathophysiolo-gy previously unexplored therapies have been used with encouraging results. In this group, acetyl-L-carnitine, alpha-lipoic-acid, cannabi-noids, clonidine, EMA401, botulinum toxin type A and new voltage-gated sodium channel blockers, can be included. Besides, changing paradigms may occur with the advent of opto-genetics and a better understanding of epige-netic regulation. We reviewed the published literature on the pharmacological treatment of NP. Despite the interesting results, random-ized controlled trials are demanded the majority of the therapies previously mentioned. In spite of several studies for the relief of NP, pain control continues being a challenge.
Allodynia and hyperalgesia suppression by a novel analgesic in experimental neuropathic pain
Biochemical and Biophysical Research Communications, 2006
SCP-1, n-[a-(benzisothiazol-3(2ho-ona,1-dioxide-2yl)-acetyl]-p-aminophenol (100 nmol), when intrathecally injected, suppressed tactile allodynia and thermal hyperalgesia in a rat neuropathic pain model. The tactile allodynia suppression lasted for at least 4 h and SCP-M1 (100 nmol), the main metabolite of SCP-1, displayed similar suppression as SCP-1, but shorter latency, indicating SCP-M1 may be the bioactive component of SCP-1. Acetaminophen was less potent than SCP-1 and SCP-M1. To study mechanisms underlying SCP-1 action, we recorded voltage-gated Ca 2+ channel currents in acutely isolated dorsal root ganglion neurons using the whole-cell patchclamp technique. SCP-1 and SCP-M1 inhibited non-L-type calcium channel currents up to 23.0 ± 2.3% and 23.1 ± 3.5%, respectively, at a depolarized pulse to À10 mV from a holding potential of À80 mV. Acetaminophen only induced 6.8 ± 1.0% inhibition. The results suggest SCP-1 possesses anti-nociceptive activity in the rat model involving calcium channel blocking properties.