title: Peripheral μ-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals.
abstract: While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects.
authors.affiliation: Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada. Electronic address: ldb874@mail.usask.ca.
authors.forename: Landon D
authors.initials: LD
authors.lastname: Baillie
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, Innsbruck A-6020, Austria. Electronic address: helmut.schmidhammer@uibk.ac.at.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
authors.affiliation: Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada. Electronic address: sean.mulligan@usask.ca.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulligan
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000344:Afferent Pathways / Q000166:cytology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005123:Eye / Q000294:innervation; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009019:Morphinans / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism*; D010147:Pain Measurement; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014276:Trigeminal Nerve / Q000502:physiology
chemical_list: C510434:2-((4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino)acetic acid; D000701:Analgesics, Opioid; D004852:Epoxy Compounds; D009019:Morphinans; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium
keywords: BK channels; Calcium imaging; N-type calcium channels; Nociceptive axon; Pain; μ-Opioid