Pain
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Comparative Study
Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains.
In a recently proposed bimodal opioid receptor model, the inhibitory actions of opioids on action potential duration in dorsal root ganglion neurons have been proposed to produce antinociception, and the excitatory actions of hyperalgesia. Recent studies indicate that selectively blocking these excitatory actions with low doses of opioid antagonists enhances opioid antinociception and attenuates the development of opioid tolerance. To determine if the excitatory actions of opioids contribute to sex as well as strain differences in opioid sensitivity, the effects of morphine alone and in combination with low doses of naltrexone were examined in male and female rats of four strains. ⋯ In male and female Sprague-Dawley and Long-Evans rats, naltrexone enhanced morphine antinociception and attenuated the development of morphine tolerance. These effects were not observed in F344 and Lewis rats, even when tests were conducted across a range of morphine and naltrexone doses. These results suggest that the ability of low doses of naltrexone to enhance opioid antinociception does not contribute to sex or rat strain differences in opioid sensitivity.
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The true incidence of neuropathic pain is unknown, but it is believed to be under-diagnosed and treated inadequately, despite the availability of drugs with proven efficacy. Our objective was to report the epidemiology and drug treatment of neuropathic pain as managed by UK primary care physicians. A descriptive analysis of the epidemiology of incident post-herpetic neuralgia (n=12,386); trigeminal neuralgia (8268); phantom limb pain (451) and painful diabetic neuropathy (4719) and prescription treatment at diagnosis from computerised UK general practice records (GPRD): January 1992 to April 2002. ⋯ In 2600 patients followed to stable therapy, there was a median of one to two drug changes. We provide the primary care managed incidence of four neuropathic pain conditions. For commonly prescribed treatments, changes in therapy are less frequent when initial therapy was with antidepressants or anticonvulsants rather than conventional analgesics.
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Chronic opioid-induced analgesic tolerance remains a major obstacle to improving clinical management of moderate to severe chronic pain. Our understanding of the underlying mechanisms for opioid tolerance is only partially understood at present. In this study, we investigated the effects of chronic morphine on GABA(A) receptor-mediated synaptic transmission, a major opioid target for pain inhibition, and the behavioral role of GABA synaptic transmission in the development of morphine tolerance. ⋯ Behaviorally, a low dose of GABA(A) receptor antagonist bicuculline microinjected into the NRM, ineffective alone, blocked morphine antinociception in control rats, but failed to do so in morphine-tolerant rats. With chronic treatment through daily NRM microinjections, bicuculline augmented the development of morphine tolerance, whereas the GABA(A) receptor agonist muscimol or H89 significantly attenuated the development of morphine tolerance. These results suggest that chronic morphine increases GABA synaptic activity through upregulation of the AMP system in morphine-tolerant NRM neurons and that while chronic GABA(A) receptor antagonism in the NRM augments morphine tolerance, chronic activation of NRM GABA(A) receptors or PKA inhibition reduces morphine tolerance with increased analgesic efficacy of chronic morphine.
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Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5-hydroxytryptamine (5-HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5-HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). ⋯ The tissue concentration of 5-HT was measured using microdialysis. Concentrations of 5-HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5-HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2A receptors.