The analgesic mechanisms of buprenorphine

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.

List of scientific papers

I. Kouya PF, Hao JX, Xu XJ (2002). Buprenorphine alleviates neuropathic pain-like behaviors in rats after spinal cord and peripheral nerve injury. Eur J Pharmacol. 450(1): 49-53.
https://pubmed.ncbi.nlm.nih.gov/12176108

II. Kouya PF, Bulka A, Hao JX, Wiesenfeld-Hallin Z, Xu XJ (2006). Pharmacological characterization of an orofacial neuropathic pain model after photochemically-induced infraorbital nerve injury: effects of morphine, buprenorphine and gabapentin. [Submitted]

III. Kouya PF, Hao JX, Xu XJ (2006). Tolerance to the antinociceptive and antiallodynic effect of buprenorphine and morphine in a rat model of mononeuropathy. [Submitted]

IV. Kouya PF, Xu XJ (2004). Buprenorphine reduces central sensitization after repetitive C-fiber stimulation in rats. Neurosci Lett. 359(1-2): 127-9.
https://pubmed.ncbi.nlm.nih.gov/15050727

V. Kouya PF, Wu WP, Wiesenfeld-Hallin Z, Xu XJ (2006). Strain differences in the antinociceptive effect of intrathecal R-phenylisopropyl-adenosine (R-PIA) and systemic buprenorphine: comaprison with morphine. [Submitted]

VI. Bulka A, Kouya PF, Bottiger Y, Svensson JO, Xu XJ, Wiesenfeld-Hallin Z (2004). Comparison of the antinociceptive effect of morphine, methadone, buprenorphine and codeine in two substrains of Sprague-Dawley rats. Eur J Pharmacol. 492(1): 27-34.
https://pubmed.ncbi.nlm.nih.gov/15145702