Ketamine-induced potentiation of morphine analgesia in rat tail-flick test: role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels.
Ketamine is known to improve opioid efficacy, reduce postoperative opioid requirement and oppose opioid associated pain hypersensitivity and tolerance. However, the mechanisms underlying these beneficial effects are not clear. This study investigated the effects of ketamine at a non-analgesic dose (30 mg/kg, i.p.) on analgesia induced by morphine (2.5, 5.0, 7.5 mg/kg, s.c.), using rat tail-flick test as an animal model of acute pain. Further, the role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels was examined on the potentiating effect of ketamine. Male rats received morphine alone at 5.0 and 7.5 but not at 2.5 mg/kg showed a dose-related increase in tail-flick latencies. The combination of morphine and ketamine resulted in dose-related increase in morphine analgesia, both on the intensity as well as on duration. The ketamine-induced potentiation of morphine (7.5 mg/kg) analgesia was unaffected by glibenclamide (3 mg/kg, s.c.) and only partially blocked by yohimbine (2 mg/kg, i.p.), but more completely abolished by naloxone (2 mg/kg, i.p.). Both morphine (5.0 mg/kg) and ketamine (30 mg/kg) alone did not evoke catalepsy in rats but on combination produced a synergistic effect, which was however, abolished by naloxone pretreatment. In the open-field test, while morphine (5.0 mg/kg) caused a depressant effect, ketamine (30 mg/kg) enhanced the locomotor activity. Nevertheless, in combination potentiated the morphine's depressant effect on locomotion, which was also antagonized by naloxone. These results indicate that ketamine at a non-analgesic dose can potentiate morphine analgesia, induce catalepsy and cause locomotor depression, possibly involving an opioid mechanism. This potentiation, although favorable in acute pain management, may have some adverse clinical implications.
Campos
Adriana Rolim
AR
Departament of Physiology and Pharmacology, Federal University of Ceara (FM), Brazil.
Santos
Flávia Almeida
FA
Rao
Vietla Satyanarayana
VS
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D004357:Drug Synergism; D054086:KATP Channels; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*
D018528:ATP-Binding Cassette Transporters; D000701:Analgesics, Opioid; D000778:Anesthetics, Dissociative; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D018341:Receptors, Adrenergic, alpha-2; D011957:Receptors, Opioid; C092520:uK-ATP-1 potassium channel; D007649:Ketamine; D009020:Morphine