title: Xenobiotic perturbation of endogenous morphine signaling: paradoxical opiate hyperalgesia.
abstract: The clinical literature has extensively documented diverse, potentially debilitating, side-effects of pharmaceutical dosages of morphine and morphine congeners administered for management of acute and chronic pain. Paradoxically, morphine is capable of engendering state-dependent hyperalgesic responses that appear to be functionally linked to secondary activation of N-methyl-D-aspartate (NMDA) receptors coupled to Ca++-evoked nitric oxide (NO) production. Similar biochemical events have been associated with the development of morphine tolerance. Recent lines of complementary evidence support both the existence and biological importance of cellular regulatory pathways mediated by endogenously synthesized, chemically authentic morphine. Cellular "morphinergic" signaling is mediated by cognate six-transmembrane helical domain (TMH) micro3 and micro4 opiate receptors linked to activation of constitutive NO synthase (cNOS). Based on the compelling association of both endogenous and exogenous morphine activation with enhanced NO production, we advance a hypothesis that morphine administered as a pharmaceutical/xenobiotic agent adversely perturbs normative "morphinergic"/NO signaling within discrete cellular microdomains. Accordingly, pharmaceutical and/or physiological disruption of basic metabolic events regulated by "morphinergic"/NO signaling is proposed to account for state-dependent morphine-mediated hyperalgesia, tolerance development, and related disruptive cellular adaptations.
authors.affiliation: Neuroscience Research Institute, State University of New York - College at Old Westbury, Old Westbury NY 11568, USA. gstefano@sunynri.org
authors.forename: George B
authors.initials: GB
authors.lastname: Stefano
authors.forename: Tobias
authors.initials: T
authors.lastname: Esch
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kream
mesh_terms: D000818:Animals; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D015262:Xenobiotics; D009020:Morphine