title: Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity.
abstract: Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six μ-agonists that varied in efficacy at μ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All μ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All μ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy μ-agonist nalbuphine, but not the high-efficacy μ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective μ-opioid analgesics and reveal distinctions between opioids based on efficacy at the μ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.
authors.affiliation: Department of Pharmacology, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan (A.A.A.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (A.A.A., S.S.N.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.) altarifiaa@vcu.edu.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Altarifi
authors.affiliation: Department of Pharmacology, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan (A.A.A.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (A.A.A., S.S.N.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.).
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Department of Pharmacology, School of Medicine, Jordan University of Science and Technology, Irbid, Jordan (A.A.A.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (A.A.A., S.S.N.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.).
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D059787:Acute Pain / Q000188:drug therapy* / Q000523:psychology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019344:Lactic Acid / Q000494:pharmacology; D008297:Male; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012653:Self Stimulation
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D019344:Lactic Acid