No antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol in male and female rats with persistent inflammatory pain

Stevie C. Britch, Rebecca M. Craft

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.

Original languageEnglish
Pages (from-to)630-639
Number of pages10
JournalBehavioural Pharmacology
Issue number8
StatePublished - Dec 1 2021

Bibliographical note

Funding Information:
This work was funded by the National Institute on Drug Abuse (T32DA035200 to S.B.), and by funds provided by a Herbert L. Eastlick Professorship (to R.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
©2021 Wolters Kluwer Health, Inc. All rights reserved.


  • THC
  • cannabis
  • drug interactions
  • inflammatory pain
  • morphine
  • opioids
  • sex differences

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology


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