The mu opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase A pathway.
BACKGROUND
The vanilloid receptor 1 (TRPV1) is critical in the development of inflammatory hyperalgesia. Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA) pathway to potentiate TRPV1-mediated capsaicin responses. Such regulation may have significance in inflammatory pain. However, few functional receptor interactions that inhibit PKA-mediated potentiation of TRPV1 responses have been described.


RESULTS
In the present studies we investigated the hypothesis that the mu opioid receptor (MOP) agonist morphine can modulate forskolin-potentiated capsaicin responses through a cAMP-dependent PKA pathway. HEK293 cells were stably transfected with TRPV1 and MOP, and calcium (Ca2+) responses to injection of the TRPV1 agonist capsaicin were monitored in Fluo-3-loaded cells. Pre-treatment with morphine did not inhibit unpotentiated capsaicin-induced Ca2+ responses but significantly altered capsaicin responses potentiated by forskolin. TRPV1-mediated Ca2+ responses potentiated by the direct PKA activator 8-Br-cAMP and the PKC activator Phorbol-12-myristate-13-acetatewere not modulated by morphine. Immunohistochemical studies confirmed that the TRPV1 and MOP are co-expressed on cultured Dorsal Root Ganglion neurones, pointing towards the existence of a functional relationship between the G-protein coupled MOP and nociceptive TRPV1.


CONCLUSIONS
The results presented here indicate that the opioid receptor agonist morphine acts via inhibition of adenylate cyclase to inhibit PKA-potentiated TRPV1 responses. Targeting of peripheral opioid receptors may therefore have therapeutic potential as an intervention to prevent potentiation of TRPV1 responses through the PKA pathway in inflammation.
Vetter
Irina
I
The School of Pharmacy, The University of Queensland, Brisbane, 4072, Australia. i.vetter@pharmacy.uq.edu.au
Wyse
Bruce D
BD
Monteith
Gregory R
GR
Roberts-Thomson
Sarah J
SJ
Cabot
Peter J
PJ
D002211:Capsaicin / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation; D017450:Receptors, Opioid, mu / Q000819:agonists*; D011994:Recombinant Proteins / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin