Catalepsy induced by combinations of ketamine and morphine: potentiation, antagonism, tolerance and cross-tolerance in the rat.
Previous studies demonstrated that both ketamine and morphine induced analgesia and catalepsy in the rat. Pre-treatment with ketamine produced cross-tolerance to morphine, whereas pretreatment with morphine did not induce cross-tolerance to ketamine but rather augmented the cataleptic response; this augmentation was attributed to residual morphine in the brain. The present studies explored the duration of the loss of righting reflex induced by sub-effective doses of ketamine and morphine, administered simultaneously. There was mutual potentiation between sub-effective doses of ketamine and morphine, but sub-effective doses of ketamine partly antagonized fully-effective doses of morphine. Latency to the loss of righting reflex, rigidity and behavior on recovery, reflected the relative predominance of ketamine or morphine in each combination. Naloxone inhibited the induced cataleptic effects. The degree and time course of development of tolerance to daily administration of sub-effective dose combinations of ketamine and morphine were similar. Rats, tolerant to ketamine-dominant combinations, were cross-tolerant to both drugs, while those tolerant to morphine-dominant combinations were cross-tolerant to morphine but showed either no cross-tolerance or an augmented response to ketamine. While the mutual potentiation, antagonism and tolerance suggest common mechanisms for the induced catalepsy, differences in latency, rigidity and behavior, asymmetry of cross-tolerance and a widely-different ID50 for naloxone would argue against an action at a single opioid site.
Hance
A J
AJ
Department of Pharmacology, School of Medicine, University of California, Davis.
Winters
W D
WD
Quam
D D
DD
Benthuysen
J L
JL
Cadd
G G
GG
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced*; D004336:Drug Antagonism; D004357:Drug Synergism; D004361:Drug Tolerance; D005260:Female; D007649:Ketamine / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects
D009270:Naloxone; D007649:Ketamine; D009020:Morphine