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Research ArticleArticle

Enhancement of μ Opioid Antinociception by Oral Δ9-Tetrahydrocannabinol: Dose-Response Analysis and Receptor Identification

Diana L. Cichewicz, Zachary L. Martin, Forrest L. Smith and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 859-867;
Diana L. Cichewicz
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Zachary L. Martin
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Forrest L. Smith
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Sandra P. Welch
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Abstract

The antinociceptive effects of various μ opioids given p.o. alone and in combination with Δ-9-tetrahydrocannabinol (Δ9-THC) were evaluated using the tail-flick test. Morphine preceded by Δ9-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED50 value when administered after Δ9-THC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone and hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, l-α-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Δ9-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Δ9-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Δ9-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Δ9-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many μ opioids are enhanced by an inactive dose of Δ9-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of μ and possibly δ opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception.

Footnotes

  • Send reprint requests to: Dr. Sandra P. Welch, P.O. Box 980613, MCV Station, Richmond, VA 23298. E-mailswelch{at}hsc.vcu.edu

  • ↵1 This work was supported by the National Institute on Drug Abuse Grants DA07027, DA05274, and K02-DA00186.

  • Abbreviations:
    Δ9-THC
    Δ-9-tetrahydrocannabinol
    nor-BNI
    nor-binaltorphimine
    % MPE
    percent maximum possible effect
    NTI
    naltrindole
    i.t.
    intrathecally
    LAAM
    l-α-acetylmethadol
    CB
    cannabinoid receptor
    • Received July 8, 1998.
    • Accepted December 15, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Enhancement of μ Opioid Antinociception by Oral Δ9-Tetrahydrocannabinol: Dose-Response Analysis and Receptor Identification

Diana L. Cichewicz, Zachary L. Martin, Forrest L. Smith and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 859-867;

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Research ArticleArticle

Enhancement of μ Opioid Antinociception by Oral Δ9-Tetrahydrocannabinol: Dose-Response Analysis and Receptor Identification

Diana L. Cichewicz, Zachary L. Martin, Forrest L. Smith and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 859-867;
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