The analgesic mechanisms of buprenorphine

Sammanfattning: Buprenorphine, a derivative of thebaine, is a semi-synthetic opiate and a partial p-opioid receptor agonist. Buprenorphine is also a weak kappa-opioid receptor antagonist. Buprenorphine is used clinically as an analgesic and for maintenance therapy of opiate-dependent subjects because it produces limited withdrawal symptoms. Recent evidence suggests that the mechanisms of the analgesic effect of buprenorphine are to large extent different from classical µ-receptor agonists. In this thesis, the analgesic mechanisms of buprenorphine are evaluated. Using animal models of neuropathic pain we showed that systemic administration of buprenorphine alleviates mechanical and cold allodynia in rats with injury to the sciatic nerve, infraorbital nerve or the spinal cord. The effect of buprenorphine is similar or superior to morphine in all three models and better than the anticonvulsant gabapentin in infraorbital nerve injured rats. Buprenorphine inhibits spinal cord hyperexcitability induced by repetitive C-fiber stimulation (central sensitization) in decerebrate, spinalized rats at a moderate dose, an effect that is not blocked by naloxone or shared by morphine. In sciatic nerve injured rats, there is a similar tolerance development to the antinociceptive effect of morphine and buprenorphine. In contrast, tolerance developed much slower to the antiallodynic effect of buprenorphine than to morphine and there is no cross-tolerance to buprenorphine in rats made tolerant to morphine. The antinociceptive effect of buprenorphine varies significantly in four inbred strains of mice (DBA2, C3H, C56BL/6 and 129). Significant between-strain differences were also seen for the antinociceptive effect of systemic morphine. The ranking order of potency was largely similar between morphine and buprenorphine in mice. On the other hand, the metabolism and antinociceptive effect of morphine, but not buprenorphine, is different in two sub-strains of Sprague-Dawley rats. The results presented in this thesis show that buprenorphine is effective in rat models of neuropathic pain. The effect of buprenorphine in nerve-injured rats may be mediated by mechanisms different from those of classic gopioid receptor agonosts and may be related to an inhibition of central sensitization. There are genetic factors in sensitivity to buprenorphine that do mot involve differences in metabolism. Buprenorphine may provide a clinical alternative in treating neuropathic pain.