Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury

Lisa M. Johanek, Donald A. Simone

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Accumulating evidence suggests that cannabinoids can produce antinociception through peripheral mechanisms. In the present study, we determined whether cannabinoids attenuated existing hyperalgesia produced by a mild heat injury to the glabrous hindpaw and whether the antihyperalgesia was receptor-mediated. Anesthetized rats received a mild heat injury (55°C for 30 s) to one hindpaw. Fifteen minutes after injury, animals exhibited hyperalgesia as evidenced by lowered withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey monofilament (200mN force) delivered to the injured hindpaw. Separate groups of animals were then treated with an intraplantar ( injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, or 30 μg in 100 μl. WIN 55,212-2 attenuated both heat and mechanical hyperalgesia dose-dependently. The inactive enantiomer WIN 55,212-3 did not alter mechanical or heat hyperalgesia, suggesting the effects of WIN 55,212-2 were receptor-mediated. The CB1 receptor antagonist AM 251 (30 μg) co-injected with WIN 55,212-2 (30 μg) attenuated the antihyperalgesic effects of WIN 55,212-2. The CB2 receptor antagonist AM 630 (30 μg) co-injected with WIN 55,212-2 attenuated only the early antihyperalgesic effects of WIN 55,212-2. injection of WIN 55,212-2 into the contralateral paw did not alter the heat-injury induced hyperalgesia, suggesting that the antihyperalgesia occurred through a peripheral mechanism. These data demonstrate that cannabinoids primarily activate peripheral CB1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CB1 receptors.

Original languageEnglish (US)
Pages (from-to)432-442
Number of pages11
Issue number3
StatePublished - Jun 2004

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (DA11471 and P30 DE09737). Lisa Johanek was supported by NIDA training grant T32 DA07234. The authors thank Dr Jim Hodges, Department of Biostatistics at the University of Minnesota, for data analysis and statistical advice, Michelle Turner for technical assistance during the experiments, and Dr Virginia Seybold for critically reading an early version of the manuscript.


  • Hyperalgesia
  • Pain
  • Rats
  • WIN 55,212-2


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