The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord

G Pugh , PB Smith, DS Dombrowski and SP Welch

Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond, USA.

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.

Volume 279, Issue 2, pp. 608-616, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				D. L. Cichewicz and S. P. Welch Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral {Delta}9-Tetrahydrocannabinol J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 812 - 817. [Abstract] [Full Text] [PDF]

				D. L. Cichewicz and E. A. McCarthy Antinociceptive Synergy between Delta 9-Tetrahydrocannabinol and Opioids after Oral Administration J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1010 - 1015. [Abstract] [Full Text] [PDF]

				V. Morisset and L. Urban Cannabinoid-Induced Presynaptic Inhibition of Glutamatergic EPSCs in Substantia Gelatinosa Neurons of the Rat Spinal Cord J Neurophysiol, July 1, 2001; 86(1): 40 - 48. [Abstract] [Full Text] [PDF]

				P. Sharpe and G. Smith Cannabis: Time for Scientific Evaluation of This Ancient Remedy? Anesth. Analg., February 1, 2000; 90(2): 237 - 237. [Full Text] [PDF]

				D. L. Cichewicz, Z. L. Martin, F. L. Smith, and S. P. Welch Enhancement of µ Opioid Antinociception by Oral Delta 9-Tetrahydrocannabinol: Dose-Response Analysis and Receptor Identification J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 859 - 867. [Abstract] [Full Text]

				S. P. Welch, J. W. Huffman, and J. Lowe Differential Blockade of the Antinociceptive Effects of Centrally Administered Cannabinoids by SR141716A J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1301 - 1308. [Abstract] [Full Text]