PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor

Amol M. Patwardhan, Anibal Diogenes, Kelly A. Berg, Jill C. Fehrenbacher, William P. Clarke, Armen N. Akopian, Kenneth M. Hargreaves

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


The role of protease activated receptor-2 (PAR-2) activation in trigeminal nociception and in induction of functional competence in the delta opioid receptor (DOR) is not known. In this study, we evaluated whether agonists of PAR-2 activate the capsaicin-sensitive subclass of trigeminal nociceptors in a PLC-PKC-dependent manner and induce functional competence in the DOR. Adult male rat trigeminal ganglion (TG) cultured neurons were treated with the PAR-2 agonist (SL-NH2) or an enzyme activator of PAR (trypsin) and the activation of TG nociceptors was assessed using three independent methods: neuropeptide release, calcium influx, and whole cell patch-clamp. The specificity of SL-NH2 and trypsin responses was evaluated using TG cultures transfected with siRNA against PAR-2. The in vivo role of PAR-2 activation was determined measuring SL-NH2 and trypsin-evoked nocifensive behavior and increase in blood flow. Trigeminal neurons were treated with SL-NH2/vehicle and then the DOR agonist to determine DOR inhibition of evoked neuropeptide release and cAMP accumulation. The results showed that SL-NH2 (100 μM) and trypsin (1-600 nM) activate TG nociceptors, which is partly reversible by the PKC inhibitor bisindolylmaleimide (500 nM) and by ruthenium red (10 μM). In cultures treated with siRNA against PAR-2, both SL-NH2 and trypsin responses were significantly diminished. Both SL-NH2 and trypsin evoke nocifensive behavior and increases in blood flow in an orofacial pain model. Application of SL-NH2 rapidly produced functional competence of DOR for inhibiting nociceptor function. In inflamed tissue, endogenous proteases may activate TG nociceptors and generate pain. Moreover, activation of PAR-2 can also induce functional competence in DOR.

Original languageEnglish (US)
Pages (from-to)114-124
Number of pages11
Issue number1-2
StatePublished - Nov 2006
Externally publishedYes


  • Delta opioid receptor
  • Pain
  • PAR, Protease activated receptor
  • RNAi
  • siRNA
  • Trigeminal
  • Trypsin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine


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