Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine

Br J Pharmacol. 2014 Feb;171(4):961-72. doi: 10.1111/bph.12488.


Background and purpose: Crotalphine is an antinociceptive peptide that, despite its opioid-like activity, does not induce some of the characteristic side effects of opioids, and its amino acid sequence has no homology to any known opioid peptide. Here, we evaluated the involvement of the peripheral cannabinoid system in the crotalphine effect and its interaction with the opioid system.

Experimental approach: Hyperalgesia was evaluated using the rat paw pressure test. Involvement of the cannabinoid system was determined using a selective cannabinoid receptor antagonist. Cannabinoid and opioid receptor activation were evaluated in paw slices by immunofluorescence assays using conformation state-sensitive antibodies. The release of endogenous opioid peptides from skin tissue was measured using a commercial enzyme immunoassay (EIA).

Key results: Both p.o. (0.008-1.0 μg·kg(-1) ) and intraplantar (0.0006 μg per paw) administration of crotalphine induced antinociception in PGE2 -induced hyperalgesia. Antinociception by p.o. crotalphine (1 μg·kg(-1) ) was blocked by AM630 (50 μg per paw), a CB2 receptor antagonist, and by antiserum anti-dynorphin A (1 μg per paw). Immunoassay studies confirmed that crotalphine increased the activation of both κ-opioid (51.7%) and CB2 (28.5%) receptors in paw tissue. The local release of dynorphin A from paw skin was confirmed by in vitro EIA and blocked by AM630.

Conclusions and implications: Crotalphine-induced antinociception involves peripheral CB2 cannabinoid receptors and local release of dynorphin A, which is dependent on CB2 receptor activation. These results enhance our understanding of the mechanisms involved in the peripheral effect of crotalphine, as well as the interaction between the opioid and cannabinoid systems.

Keywords: CB2 cannabinoid receptors; antinociception; cannabinoid-opioid interaction; crotalphine; dynorphin A; endogenous opioid release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Analgesics / therapeutic use
  • Animals
  • Cannabinoid Receptor Antagonists / pharmacology
  • Dinoprostone
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism*
  • Indoles / pharmacology
  • Male
  • Opioid Peptides / metabolism*
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Skin / drug effects*
  • Skin / metabolism


  • Analgesics
  • Cannabinoid Receptor Antagonists
  • Indoles
  • Opioid Peptides
  • Peptides
  • Receptor, Cannabinoid, CB2
  • crotalphine
  • Dinoprostone
  • iodopravadoline