Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine-Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice.
Previous studies showed that cannabinoids administered intrathecally (i.t.) produced antinociception and synergism with the antinociceptive effects of morphine. Low doses of naloxone that appear selective for the mu receptor failed to block the antinociceptive effect of the cannabinoids. The present studies evaluated the interaction of the cannabinoids with kappa and delta opioid antagonists and agonists. Antinociception produced by delta 9 tetrahydrocannabinol (THC) and delta 8-THC (i.v., ED80 doses) was blocked by the kappa antagonist, nor-BNI (10 and 20 micrograms/mouse). The effects of CP 55,940 administered i.v. were blocked by norbinaltorphimine (nor-BNI; i.v. but not i.t.). The delta antagonist, N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864; 10 micrograms/mouse administered i.t.), failed to block the effects of any of the cannabinoids administered i.v. Nor-BNI administered i.t. blocked the antinociception produced by the cannabinoids (administered i.t., ED80 doses). The AD50s generated for nor-BNI vs. i.t. administered delta 9-THC, delta 8-THC, levonantradol and CP 55,940 were 3.5, 1.1, 3.8 and 4.5 micrograms/mouse, respectively. Nor-BNI (10 micrograms/mouse i.t.) shifted the dose-effect curve for delta 9-THC to the right in a parallel manner. delta 9-THC was additive with the kappa agonist, U50,488H, whereas delta 9-THC produced a parallel 37-fold shift to the left in the dose-effect curve of the delta agonist, DPDPE. Nor-BNI (70 micrograms/mouse i.c.v.) or ICI 174,864 (10 micrograms/mouse i.t.) failed to block the effects of the cannabinoids administered i.t. The exact nature of the nor-BNI/cannabinoid interaction is yet to be determined.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia, Richmond.
S P
SP
Welch
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D013759:Dronabinol / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D007262:Infusions, Intravenous; D007278:Injections, Spinal; D051379:Mice; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000187:drug effects
D000700:Analgesics; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D009270:Naloxone; C051844:norbinaltorphimine; D004743:Enkephalin, Leucine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D013759:Dronabinol; D020881:Enkephalin, D-Penicillamine (2,5)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine