Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine.

Background and purpose: Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl. Experimental approach: The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G_z protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally. Key results: Spinal naloxone (20 µg) or PTX (1 µg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G_z protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G_z-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G_z-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mg·kg⁻¹, i.p.) enhanced the ascending (3 mg·kg⁻¹) and descending (30 mg·kg⁻¹) portions of buprenorphine's dose–response curve, but only spinal, not supraspinal, nociceptin (10 nmol·L⁻¹) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001–10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg·kg⁻¹, s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception. Conclusions and implications: Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G_z protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine. [ABSTRACT FROM AUTHOR]