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Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine
Author(s) -
Ding Zhe,
Raffa Robert B
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00209.x
Subject(s) - buprenorphine , pharmacology , nociception , (+) naloxone , nociceptin receptor , morphine , fentanyl , opioid , medicine , chemistry , anesthesia , opioid peptide , receptor
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.