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While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB(1) receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain. Systemic administration of URB597 (0.3 mg kg(-1)) and HU210 (0.03 mg kg(-1)) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve-ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats. The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB1 antagonist AM251 (1 mg kg(-1)), or the CB2 and SR144528 (1 mg kg(-1)). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597. These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB1 and CB2 receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.

Background and Purpose: Antagonists of the N-type voltage gated calcium channel (VGCC), Cav 2.2, have a potentially important role in the treatment of chronic neuropathic pain. ω-conotoxins, such MVIIA and CVID are effective in neuropathic pain models. CVID is reported to have a greater therapeutic index than MVIIA in neuropathic pain models, and it has been suggested that this is due to faster reversibility of binding, but it is not known whether this can be improved further.Experimental Approach: We examined the potency of CVID, MVIIA and two intermediate hybrids ([K10R]CVID and [R10K]MVIIA) to reverse signs of neuropathic pain in a rat nerve ligation model in parallel with production of side effects. We also examined the potency and reversibility to inhibit primary afferent synaptic neurotransmission in rat spinal cord slices.Key Results: All ω-conotoxins produced dose-dependent reduction in mechanical allodynia. They also produced side effects on the rotarod test and in a visual side-effect score. CVID displayed a marginally better therapeutic index than MVIIA. The hybrids had a lesser effect in the rotarod test than either of their parent peptides. Finally, the conotoxins all presynaptically inhibited excitatory synaptic neurotransmission into the dorsal horn and displayed recovery that was largely dependent upon the magnitude of inhibition and not the conotoxin type.Conclusions and Implications: These findings indicate that CVID provides only a marginal improvement over MVIIA in a preclinical model of neuropathic pain, which appears to be unrelated to reversibility from binding. Hybrids of these conotoxins might provide viable alternative treatments. [ABSTRACT FROM AUTHOR]

P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain.Naloxone (1–10 mg kg−1, i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1–300 μmol kg−1, s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5–L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg−1, s.c.) in each of these behavioral models.Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg−1, i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10–50 nmol) and systemically (10 mg kg−1, i.p.) administered naloxone.This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone.In in vitro studies, A-317491 (3–100 μM) did not produce any agonist response at δ opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the κ and μ opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors.Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.British Journal of Pharmacology (2005) 146, 180–188. doi:10.1038/sj.bjp.0706346; published online 25 July 2005 [ABSTRACT FROM AUTHOR]

1 We have recently reported that systemic delivery of A-317491, the first non-nucleotide antagonist that has high affinity and selectivity for blocking P2X[sub3] homomeric and P2X[sub2/3], heteromeric channels, is antinociceptive in rat models of cionhronic inflammatory and neuropathic pain, In an effort to further evaluate the role of P2X[sub3]/P2X[sub2/3] receptors in nociceptive transmission, A-317491 was administered either intrathecally or into the hindpaw of a rat in several models of acute and chronic nociception. 2 Intraplantar (ED[sub50] = 300nmol) and intrathecal (ED[sub50] = 30nmol) injections of A-317491 produced dose-related antinociception in the CFA model of chronic thermal hyperalgesia. Administration of A-317491 by either route was much less effective to reduce thermal hyperalgesia in the carrageenan model of acute inflammatory hyperalgesia. 3 Intrathecal, but not intraplantar, delivery of A-317491 attenuated mechanical allodynia in both the chronic constriction injury and L5-L6 nerve ligation models of neuropathy (ED[sub50] = 10 nmol for both models). Intrathecal injections of A-317491 did not impede locomotor performance. 4 Both routes of injection were effective in reducing the number of nocifensive events triggered by the injection of formalin into a hindpaw. Nocifensive behaviors were significantly reduced in both the first and second phases of the formalin assay (intrathecal ED[sub50] = 10 nmol, intraplantar ED[sub50] > 300 nmol). Nocifensive behaviors induced by the P2X receptor agonist α,β-meATP were also significantly reduced by intraplantar injection of A-317491. 5 These data indicate that both spinal and peripheral P2X[sub3],P2X[sub2/3] receptors have significant contributions to nociception in several animal models of nerve or tissue injury. Intrathecal administration of A-317491 appears to be more effective than intraplantar administration to reduce tactile allodynia following peripheral nerve injury [ABSTRACT FROM AUTHOR]