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 journalArticle

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Abstract

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
JournalPain
Volume125
Issue number1-2
DOIs
StatePublished - Nov 2006
Externally publishedYes

Fingerprint

PAR-2 Receptor
Nociceptors
delta Opioid Receptor
Mental Competency
Trigeminal Ganglion
Trypsin
Neuropeptides
Small Interfering RNA
Enzyme Activators
Neurons
Ruthenium Red
Facial Pain
Nociception
seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
Capsaicin
Peptide Hydrolases
Calcium
Pain

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neurology
  • Neuroscience(all)
  • Pharmacology
  • Clinical Psychology

Cite this

Patwardhan, A. M., Diogenes, A., Berg, K. A., Fehrenbacher, J. C., Clarke, W. P., Akopian, A. N., & Hargreaves, K. M. (2006). PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor. Pain, 125(1-2), 114-124. https://doi.org/10.1016/j.pain.2006.05.007

PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor. / Patwardhan, Amol M; Diogenes, Anibal; Berg, Kelly A.; Fehrenbacher, Jill C.; Clarke, William P.; Akopian, Armen N.; Hargreaves, Kenneth M.

In: Pain, Vol. 125, No. 1-2, 11.2006, p. 114-124.

Research output: Contribution to journalArticle

Patwardhan, AM, Diogenes, A, Berg, KA, Fehrenbacher, JC, Clarke, WP, Akopian, AN & Hargreaves, KM 2006, 'PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor', Pain, vol. 125, no. 1-2, pp. 114-124. https://doi.org/10.1016/j.pain.2006.05.007
Patwardhan, Amol M ; Diogenes, Anibal ; Berg, Kelly A. ; Fehrenbacher, Jill C. ; Clarke, William P. ; Akopian, Armen N. ; Hargreaves, Kenneth M. / PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor. In: Pain. 2006 ; Vol. 125, No. 1-2. pp. 114-124.
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