Sex differences in the development of localized and spread mechanical hypersensitivity in rats after injury to the infraorbital or sciatic nerves to create a model for neuropathic pain.

BACKGROUND: Neuropathic pain after injury to the nervous system is a difficult clinical problem. Sex differences in the development of neuropathic pain have not been well established experimentally or clinically. OBJECTIVE: Rats were used to examine sex differences in localized and spread mechanical hypersensitivity after partial injury to their infraorbital or sciatic nerves in a model of neuropathic pain. METHODS: In adult female and male rats, partial nerve injury to the infraorbital and sciatic nerves was produced using a photochemical method. Mechanical hypersensitivity (allodynia) was examined and compared in the innervation territories of the nerves on the face or hind paw. The spread of hypersensitivity beyond the innervation territories of the injured nerves was also studied. The female and male rats were randomized to active and sham groups. The rats in the sham group had their sciatic or infraorbital nerve exposed, but not injured. RESULTS: A total of 67 rats (36 females, 31 males) were used. There was a marked sex difference in the response to infraorbital nerve injury: female rats developed more profound and long-lasting facial hypersensitivity than did male rats (P<0.001). Hypersensitivity of the hind paw after sciatic nerve injury did not, however, significantly differ between female and male rats. Spread mechanical hypersensitivity was noted in body areas outside the innervation territory of the injured nerve. This hypersensitivity was more profound after infraorbital than sciatic nerve injury and also displayed a significant sex difference (female>male, P < 0.001). Sham-group rats did not exhibit localized or spread mechanical hypersensitivity. CONCLUSION: Sex differences in the development of neuropathic painlike behaviors in rats were dependent on site of injury and site of testing, with female rats being more susceptible to the development of spread mechanical hypersensitivity, particularly after facial nerve injury, compared with male rats.

Behavioral changes and trigeminal ganglion sodium channel regulation in an orofacial neuropathic pain model.

We used a photochemical method to generate a partial ischemic injury to the infraorbital branch of the trigeminal nerve in rats. Following injury, rats developed a bilateral persistent hypersensitivity to mechanical stimulation in the territory innervated by the infraorbital nerve. In addition, spread of mechanical hypersensitivity beyond the facial region was noted. Heat hypersensitivity was also present, although to a lesser extent and of a shorter duration. In some rats, excessive facial grooming/scratching were observed. Morphological examination revealed a graded damage to the irradiated portion of the infraorbital nerve that was related to the duration of laser irradiation. Investigations of gene expression changes in injured trigeminal ganglion neurons of animals with behavioral signs of neuropathic pain demonstrated that the sodium channel alpha-subunit Na(v)1.3-absent in sham-operated animals-was expressed to a limited extent. mRNAs for Na(v)1.8 and Na(v)1.9 were reduced both with respect to proportions of expressing neurons and to intensities, whereas the beta 3 subunit was markedly upregulated. mRNA levels of p11, a regulatory factor that facilitates the surface expression of Na(v)1.8, were unchanged. Previous findings have shown that injury to the trigeminal nerve branches may elicit responses that differ from those of segmental spinal nerves. Despite this we conclude that the key sodium channel regulations that are reported as consequences of nerve damage in the dorsal root ganglia seem to appear also in the trigeminal ganglion. Thus, novel analgesic drugs designed to target the sodium channel subtypes involved could be of use for the treatment of orofacial pain.

Comparison of the antinociceptive effect of morphine, methadone, buprenorphine and codeine in two substrains of Sprague-Dawley rats.

Sprague-Dawley rats from two different vendors, Möllegård, Denmark and B&K Universal, Sweden, have been tested for the antinociceptive effect of morphine, methadone, buprenorphine and codeine on the hot plate. Morphine and methadone had significantly weaker effect in Möllegård rats compare to B&K rats. In contrast, the effect of buprenorphine was stronger in Möllegård rats than in B&K rats and the effect of codeine was similar in the two substrains. Plasma levels of morphine, morphine-6-glucuronide, morphine-3-glucuronide, buprenorphine and norbuprenorphine were determined at two time points after drug injection. Möllegård rats had significantly lower mean plasma level of morphine and significantly higher ratio of morphine-3-glucuronide/morphine at 30 min, compared to B&K rats. No difference was seen for the metabolism of buprenorphine in the two substrains. The results suggest that Möllegård rats metabolize morphine to morphine-3-glucuronide to a greater extent than B&K rats, and this may at least partly underlie the substrain difference in the effect of morphine. It is also suggested that the antinociceptive mechanisms of buprenorphne may be different from those of morphine and methadone.

Buprenorphine reduces central sensitization after repetitive C-fiber stimulation in rats.

The partial micro-opioid receptor agonist buprenorphine produces antinociception through mechanisms different from those of classical opioids. In this study, we compared the effect of buprenorphine and morphine on C-fiber conditioning stimulation (CS)-induced facilitation of the flexor reflex, a model of central sensitization in decerebrate, spinalized unanesthetized rats. Intraperitoneal morphine and buprenorphine moderately depressed the baseline flexor reflex to a similar extent at doses of 1-2 and 0.03-0.1 mg/kg, respectively. Buprenorphine significantly reduced C-fiber CS-induced reflex facilitation whereas morphine at 1 or 2 mg/kg had no effect. Thus, some of the atypical antinociceptive effects of buprenorphine may be derived from its effect on central sensitization.

Buprenorphine alleviates neuropathic pain-like behaviors in rats after spinal cord and peripheral nerve injury.

We have studied and compared the antinociceptive and anti-hyperalgesic effect of the partial opioid receptor agonist buprenorphine in normal and neuropathic rats. In normal rats, systemic buprenorphine produced dose-dependent antinociception on the hot plate test. In rats with peripheral nerve or spinal cord injury, buprenorphine markedly alleviated neuropathic pain-related behaviors, including mechanical and cold allodynia/hyperalgesia at doses comparable to that producing antinociception. The results suggest that buprenorphine may be a useful analgesic for treating neuropathic pain and thus is an atypical opioid since morphine tends to be less potent after nerve injury.