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


METHODS
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.


RESULTS
Spinal naloxone (20 microg) or PTX (1 microg) 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 mgxkg(-1), i.p.) enhanced the ascending (3 mgxkg(-1)) and descending (30 mgxkg(-1)) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmolxL(-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 mgxkg(-1), s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.


CONCLUSIONS
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.
Ding
Zhe
Z
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Raffa
Robert B
RB
D000109:Acetylcholine; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000634:Aminoquinolines / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000779:Anesthetics, Local / Q000008:administration & dosage; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002047:Buprenorphine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005283:Fentanyl / Q000008:administration & dosage; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D019319:Okadaic Acid / Q000008:administration & dosage; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D037342:Pertussis Toxin / Q000008:administration & dosage; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*; D015016:Yohimbine / Q000008:administration & dosage; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000109:Acetylcholine; D000317:Adrenergic alpha-Antagonists; D000634:Aminoquinolines; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D001549:Benzamides; D002047:Buprenorphine; D004791:Enzyme Inhibitors; D005283:Fentanyl; D019204:GTP-Binding Proteins; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D019319:Okadaic Acid; D016376:Oligonucleotides, Antisense; D018847:Opioid Peptides; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases; D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D011957:Receptors, Opioid; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D015016:Yohimbine; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C000722287:Oprl1 protein, mouse