Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide

Theodore J. Price, Amol Patwardhan, Armen N. Akopian, Kenneth M. Hargreaves, Christopher M. Flores

Research output: Contribution to journalArticlepeer-review

130 Scopus citations


1 Peripheral cannabinoids have been shown to suppress nociceptive neurotransmission in a number of behavioral and neurophysiological studies. It is not known, however, whether cannabinoids exert this action through direct interactions with nociceptors in the periphery and/or if other processes are involved. To gain a better understanding of the direct actions of cannabinoid-vanilloid agonists on sensory neurons, we examined the effects of these compounds on trigeminal ganglion (TG) neurons in vitro. 2 AEA (EC 50 = 11.0 μM), NADA (EC 50 = 857 nM) and arachidonyl-2-chloroethylamide ACEA (EC 50 = 14.0 μM) each evoked calcitonin gene-related peptide (CGRP) release from TG neurons. The TRPV1 antagonists iodo-resiniferatoxin (I-RTX) and capsazepine (CPZ) each obtunded AEA-, NADA-, ACEA- and capsaicin (CAP)-evoked CGRP release with individually equivalent IC 50's for each of the compounds (I-RTX IC 50 range = 2.6-4.0 nM; CPZ IC 50 range = 523-1140 μM). 3 The pro-inflammatory mediator prostaglandin E 2 significantly increased the maximal effect of AEA-evoked CGRP release without altering the EC 50. AEA, ACEA and CAP stimulated cAMP accumulation in TG neurons in a calcium- and TRPV1-dependent fashion. Moreover, the protein kinase inhibitor staurosporine significantly inhibited AEA- and CAP-evoked CGRP release. 4 The pungency of AEA, NADA, ACEA and CAP in the rat eye-wipe assay was also assessed. Interestingly, when applied intraocularly, NADA or CAP each produced nocifensive responses, while AEA or ACEA did not. 5 Finally, the potential inhibitory effects of these cannabinoids on TG nociceptors were evaluated. Neither AEA nor ACEA decreased CAP-evoked CGRP release. Furthermore, neither of the cannabinoid receptor type 1 antagonists SR141716A nor AM251 had any impact on either basal or CAP-evoked CGRP release. AEA also did not inhibit 50 mM K +-evoked CGRP release and did not influence bradykinin-stimulated inositol phosphate accumulation. 6 We conclude that the major action of AEA, NADA and ACEA on TG neurons is excitatory, while, of these, only NADA is pungent. These findings are discussed in relation to our current understanding of interactions between the cannabinoid and vanilloid systems and nociceptive processing in the periphery.

Original languageEnglish (US)
Pages (from-to)1118-1130
Number of pages13
JournalBritish Journal of Pharmacology
Issue number7
StatePublished - Apr 2004


  • Anandamide
  • Arachidonyl-2-chloroethylamide
  • Calcitonin gene-related peptide
  • Cannabinoid
  • Pain
  • Sensory neuron
  • Transient receptor potential
  • Trigeminal ganglion
  • Vanilloid
  • n-arachidonoyl- dopamine

ASJC Scopus subject areas

  • Pharmacology


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