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Pannexin 1 (panx1) is a large-pore membrane channel expressed in many tissues of mammals, including neurons and glial cells. Panx1 channels are highly permeable to calcium and adenosine triphosphatase (ATP); on the other hand, they can be opened by ATP and glutamate, two crucial molecules for acute and chronic pain signaling in the spinal cord dorsal horn, thus suggesting that panx1 could be a key component for the generation of central sensitization during persistent pain. In this study, we examined the effect of three panx1 blockers, namely, 10panx peptide, carbenoxolone, and probenecid, on C-reflex wind-up activity and mechanical nociceptive behavior in a spared nerve injury neuropathic rat model involving sural nerve transection. In addition, the expression of panx1 protein in the dorsal horn of the ipsilateral lumbar spinal cord was measured in sural nerve-transected and sham-operated control rats. Sural nerve transection resulted in a lower threshold for C-reflex activation by electric stimulation of the injured hindpaw, together with persistent mechanical hypersensitivity to pressure stimuli applied to the paw. Intrathecal administration of the panx1 blockers significantly depressed the spinal C-reflex wind-up activity in both neuropathic and sham control rats, and decreased mechanical hyperalgesia in neuropathic rats without affecting the nociceptive threshold in sham animals. Western blotting showed that panx1 was similarly expressed in the dorsal horn of lumbar spinal cord from neuropathic and sham rats. The present results constitute the first evidence that panx1 channels play a significant role in the mechanisms underlying central sensitization in neuropathic pain.

The aim of this study was to develop a rat model of capsaicin-induced pain in the orofacial region. We examined the effects of subcutaneous injection of different doses of capsaicin (0.25, 0.4, 0.8, 1.5, 2.5, 25, 50, 100, 500 microg) on the face-grooming response. Injection of capsaicin into the vibrissa pad produced an immediate grooming of the injected area with ipsilateral fore- or hindpaw. A positive relationship between the amplitude of the grooming response and the capsaicin dose was observed until 1.5 microg, but with the highest concentrations (ranging from 25 to 500 microg) the amplitude of the response decreased. Morphine administered either systemically (in the neck, 0.5-4.0 mg/kg) or locally (0.25-1.0 mg/kg) reduced in a dose-dependent fashion the face grooming provoked by subcutaneous capsaicin (1.5 microg). The systemic and local morphine effects could be reversed by systemic (0.1 mg/kg) and local (0.05 mg/kg) administration of naloxone, respectively. The local administration of morphine (ED(50): 0.65 mg/kg) was more potent than systemic injection (ED50: 2.54 mg/kg) in reducing the grooming behavior. In conclusion, the orofacial capsaicin test appears to be a valid and reliable method for studying trigeminal pain mechanisms and testing analgesic drugs. The results of the present study also support the clinical use of peripheral opioid administration for the treatment of orofacial painful conditions.

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Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.

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