title: Interaction between morphine and norketamine enantiomers in rodent models of nociception.
abstract: Ketamine, one of a few clinically-available N-Methyl-D-aspartate (NMDA)-receptor antagonists, is known to improve the analgesic efficacy of opioids in humans and rodents. However, the use of ketamine in combination with opioids is mainly restricted to the perioperative setting, due to severe psychotomimetic, sedative and motor side effects. Recent data from our laboratory demonstrated that a major metabolite of ketamine, norketamine, in particular the S(+) enantiomer, had a better antinociception/side effects profile than ketamine in rats. It is unknown if norketamine affects opioid antinociception. In the present study, morphine (a low dose) was combined with S(+)- and R(-)-norketamine (sub-antinociceptive doses) and characterized utilizing rodent models of pain including: thermal nociception (the tail-flick test), peripheral neuropathy (chronic constriction nerve injury) and tonic inflammatory pain (the formalin test). The data showed that: 1) Norketamine enhanced morphine antinociception and blocked tolerance to this effect; 2) Norketamine potentiated morphine effectiveness in the alleviation of symptoms resulting from injury to nerve (mechanical hyperalgesia, tactile allodynia) and peripheral tissue (formalin-induced nociceptive behavior); 3) S(+)-norketamine was more potent than R(-)-norketamine; 4) Antinociception was not confounded by significant side effects. Morphine-S(+)-norketamine combination drug therapy may prove clinically useful for the alleviation of acute and chronic pain of differing etiology.
authors.affiliation: University of Kentucky, College of Medicine, Department of Anesthesiology, UKMC, 800 Rose Street, N-202, Lexington, KY 40536-0293, USA. jrhol2@email.uky.edu
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Holtman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Jaime
authors.initials: J
authors.lastname: Johnson-Hardy
authors.forename: Elzbieta P
authors.initials: EP
authors.lastname: Wala
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003251:Constriction, Pathologic / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D005557:Formaldehyde; D007649:Ketamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000701:Analgesics, Opioid; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D005557:Formaldehyde; D007649:Ketamine; D009020:Morphine; C033419:norketamine