title: Pleiotropic opioid regulation of spinal endomorphin 2 release and its adaptations to opioid withdrawal are sexually dimorphic.
abstract: We studied adaptations to acute precipitated opioid withdrawal of spinal μ-opioid receptor (MOR)-coupled regulation of the release of endomorphin 2 (EM2). The release of this highly MOR-selective endogenous opioid from opioid-naive spinal tissue of male rats is subjected to MOR-coupled positive as well as negative modulation via cholera toxin-sensitive G(s) and pertussis toxin-sensitive G(i)/G(o), respectively. The net effect of this concomitant bidirectional modulation is inhibitory. MOR-coupled pleiotropic regulation of EM2 release is retained in opioid-withdrawn spinal tissue of male rats, but the balance of MOR-coupled inhibitory and facilitatory regulation shifted such that facilitatory regulation predominates. Augmented coupling of MOR to G(s) is causally associated with this change. Strikingly, pleiotropic characteristics of MOR-coupled regulation of spinal EM2 release and adaptations thereof to opioid withdrawal are male-specific. In females, MOR-coupled regulation of EM2 release from opioid-naive and -withdrawn spinal tissue does not have a significant G(s)-coupled facilitatory component, and MOR-coupled inhibition of EM2 release persists unabated in withdrawn preparations. The male-specific adaptations to chronic morphine that shift the relative predominance of opposing dual G protein-coupled MOR pathways provides a mechanism for mitigating inhibitory MOR signaling without losing MOR-coupled feedback regulation. These adaptations enable using endogenous EM2 as a substitute for morphine that had been precipitously removed. The sexually dimorphic functionality and regulation of spinal EM2/MOR-coupled signaling suggest the clinical utility of using sex-specific treatments for addiction that harness the activity of endogenous opioids.
authors.affiliation: Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Nai-Jiang
authors.initials: NJ
authors.lastname: Liu
authors.forename: James E
authors.initials: JE
authors.lastname: Zadina
authors.forename: Tarak
authors.initials: T
authors.lastname: Sharma
authors.forename: Alan R
authors.initials: AR
authors.lastname: Gintzler
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002772:Cholera Toxin / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000502:physiology*; D005260:Female; D047468:Immunoprecipitation; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism*; D010477:Perfusion; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012727:Sex Characteristics; D013131:Spine / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D017409:Sufentanil / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D009020:Morphine; D002772:Cholera Toxin; D017409:Sufentanil; D037342:Pertussis Toxin; D054648:Protein Phosphatase 2