The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord.
We have shown previously that intrathecal (i.t.) administration of the combination of delta 9-tetrahydrocannabinol (THC) and morphine results in a greater than additive antinociceptive effect. Similarly, pretreating mice with subthreshold doses of the kappa agonist, Dynorphin A (1-8), produced a parallel, leftward shift of the morphine dose-response curve, shifting the ED50 of morphine from 0.32 to 0.04 micrograms/mouse. A cocktail of enzyme inhibitors used to prevent the metabolism of Dynorphin A (1-8) into the delta receptor agonist, [Leu5]-enkephalin, attenuated the enhancement of morphine-induced antinociception by delta 9-THC. The enhanced antinociceptive effect observed after i.t. administration of the combination of delta 9-THC and morphine was also attenuated with antisera to Dynorphin A (1-8) (10 micrograms/ mouse) and Dynorphin A (1-13) (10 micrograms/mouse). Antisera to Dynorphin A (1-8) and Dynorphin A (1-17) blocked the antinociceptive effects of delta 9-THC (50 micrograms i.t.) without producing any significant alteration in the hypothermic and cataleptic effects or hypomotility produced by delta 9-THC. The antinociception produced by the combination of delta 9-THC and morphine was blocked by the kappa antagonist, nor-binaltorphimine (2 micrograms/ mouse), as well as the delta antagonist, naltrindole (5 micrograms/ mouse). Thus, the antinociception of morphine, which is mediated predominately by mu receptors, may be enhanced by delta 9-THC through the activation of kappa and delta receptors.
Pugh
G
G
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond, USA.
Smith
P B
PB
Dombrowski
D S
DS
Welch
S P
SP
D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D013759:Dronabinol / Q000494:pharmacology*; D004357:Drug Synergism; D004399:Dynorphins / Q000502:physiology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology
D000700:Analgesics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D004399:Dynorphins; D009020:Morphine; D013759:Dronabinol; D002118:Calcium