buprenorphine and naloxonazine

Due to its distinct pharmacological profile and lower incidence of adverse events compared with other opioids, buprenorphine is considered a safe option for pain and substitution therapy. However, despite its wide clinical use, little is known about the synaptic effects of buprenorphine in nociceptive pathways. Here, we demonstrate dose-dependent, bimodal effects of buprenorphine on transmission at C-fiber synapses in rat spinal cord dorsal horn in vivo. At an analgesically active dose of 1500 μg·kg(-1), buprenorphine reduced the strength of spinal C-fiber synapses. This depression required activation of spinal opioid receptors, putatively μ1-opioid receptors, as indicated by its sensitivity to spinal naloxone and to the selective μ1-opioid receptor antagonist naloxonazine. In contrast, a 15,000-fold lower dose of buprenorphine (0.1 μg·kg(-1)), which caused thermal and mechanical hyperalgesia in behaving animals, induced an enhancement of transmission at spinal C-fiber synapses. The ultra-low-dose buprenorphine-induced synaptic facilitation was mediated by supraspinal naloxonazine-insensitive, but CTOP-sensitive μ-opioid receptors, descending serotonergic pathways, and activation of spinal glial cells. Selective inhibition of spinal 5-hydroxytryptamine-2 receptors (5-HT2Rs), putatively located on spinal astrocytes, abolished both the induction of synaptic facilitation and the hyperalgesia elicited by ultra-low-dose buprenorphine. Our study revealed that buprenorphine mediates its modulatory effects on transmission at spinal C-fiber synapses by dose dependently acting on distinct μ-opioid receptor subtypes located at different levels of the neuraxis.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Astrocytes; Buprenorphine; Dose-Response Relationship, Drug; Hyperalgesia; In Vitro Techniques; Male; Naloxone; Nerve Fibers, Unmyelinated; Pain Measurement; Pain Threshold; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord; Spinal Nerve Roots; Synapses; Time Factors

The antinociceptive effect of buprenorphine was examined in mu1-opioid receptor-deficient CXBK mice. I.p. administration of buprenorphine at a dose of 3 mg/kg produced marked antinociception in the tail-flick test in C57BL/6 mice, a progenitor strain of CXBK mice. The antinociceptive effect of buprenorphine in C57BL/6 mice was antagonized by pretreatment with either beta-funaltrexamine (beta-FNA), a mu-opioid receptor antagonist, or naloxonazine (NXZ), a selective mu1-opioid receptor antagonist. The antinociceptive effect of buprenorphine (3 mg/kg, i.p.) in CXBK mice was significantly less than that in C57BL/6 mice. Neither beta-FNA nor NXZ reduced the antinociceptive effect of buprenorphine in CXBK mice. There was no significant difference between the buprenorphine-induced antinociceptive effect in CXBK mice and NXZ-treated C57BL/6 mice. Furthermore, neither naltrindole, a selective delta-opioid receptor antagonist, nor norbinaltorphimine, a selective kappa-opioid receptor antagonist, had a significant effect on the antinociceptive effects of buprenorphine in both CXBK and C57BL/6 mice. These results support our previous hypothesis that mu1- rather than mu2-, delta- or kappa-opioid receptors are involved in the antinociceptive effects of buprenorphine.

Topics: Animals; Buprenorphine; Male; Mice; Mice, Inbred C57BL; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu; Species Specificity

The effect of buprenorphine on the antitussive effect of morphine was examined in mice. Buprenorphine at doses of 0.1, 0.3 and 1 mg/kg given i.p. alone have no effects on the % inhibition in the number of capsaicin-induced coughs. However, pretreatment with the same doses of buprenorphine for 2 hr significantly attenuated the antitussive effect of morphine (3 mg/kg, i.p.). Naloxonazine, a selective mu 1-opioid receptor antagonist, had no effect of buprenorphine on antitussive effect of morphine. These results suggest that buprenorphine antagonizes the antitussive effect of morphine via the activation of mu 1-opioid receptors.

Topics: Animals; Antitussive Agents; Buprenorphine; Capsaicin; Cough; Injections, Intraperitoneal; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Receptors, Opioid, mu; Time Factors