Effects of nor-binaltorphimine on butorphanol dependence.
Butorphanol has been shown to act on mu-, delta-, and kappa-opioid receptors. However, the relative involvement of different opioid receptor subtypes in butorphanol dependence is not known. In the present study, nor-binaltorphimine, a long-acting non-peptide kappa-opioid receptor antagonist, was employed to mask central kappa-opioid receptors before and during the induction of butorphanol dependence in rats, so that the involvement of kappa-opioid receptors could be elucidated. The results revealed that treatment with nor-binaltorphimine markedly blocked naloxone-precipitated withdrawal signs of escape behavior, teeth-chattering, wet shakes, ptosis, body weight loss, and hypothermia at all doses tested, and attenuated the withdrawal symptoms of forepaw tremors (24 nmol: P < 0.001) and diarrhea (12 nmol: P < 0.05; 24 nmol: P < 0.01). In contrast, nor-binaltorphimine had no effect on yawning, ejaculation, nor urination in butorphanol-infused rats undergoing withdrawal. Three days of butorphanol infusion significantly increased KD values (in the cortex and striatum), decreased Bmax (in the cortex only) of [3H]U-69,593 binding, and shifted Ki of nor-binaltorphimine against [3H]U-69,593 (4.5 nM) binding in the cortex by more than 10-fold. Treatment with nor-binaltorphimine blocked the effects of butorphanol on kappa-opioid receptors. It is therefore concluded that kappa-opioid receptors are involved in mediating escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, weight loss, and hypothermia in butorphanol-dependent rats undergoing withdrawal. Furthermore, kappa-opioid receptors become desensitized to agonists (in the cortex and striatum), down-regulated (in the cortex), and supersensitive to antagonists in butorphanol-dependent rats.
Jaw
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SP
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216.
Makimura
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Hoskins
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D000818:Animals; D044482:Benzeneacetamides; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002077:Butorphanol; D003967:Diarrhea; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004924:Escape Reaction / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000503:physiopathology*; D014202:Tremor
D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051843:binaltorphimine; D009271:Naltrexone; C045444:U 69593; D002077:Butorphanol