title: Chronic morphine-induced loss of the facilitative interaction between vasoactive intestinal polypeptide and delta-opioid: involvement of protein kinase C and phospholipase Cbetas.
abstract: This laboratory recently demonstrated a multiplicative interaction between the pelvic visceral afferent transmitter vasoactive intestinal polypeptide (VIP) and the delta-opioid receptor (DOR)-selective agonist [D-Pen2,5] enkephalin (DPDPE) to regulate cAMP levels in spinal cord [Brain Res. 959 (2003) 103]. Although DOR activation is required for the manifestation of the VIP-DPDPE facilitative interaction, its relevance to opioid antinociception remains unclear. The current study investigates whether or not the VIP-DPDPE facilitation of cAMP formation is subject to tolerance formation, a hallmark characteristic of opioid antinociception. Chronic morphine exposure abolishes the VIP-DPDPE facilitative interaction, consistent with its relevance to DOR antinociception. However, acute in vitro inhibition of protein kinase C (PKC) reinstates the VIP-DPDPE multiplicative interaction characteristic of opioid naïve spinal tissue. This suggests that its chronic morphine-induced loss requires a PKC phosphorylation. PKC phosphorylation negatively modulates phospholipase C (PLC)beta, enzymes intimately associated with phosphoinositide turnover and calcium trafficking. These are essential determinants of acute and chronic opioid effects. Accordingly, the effect of chronic morphine on their state of phosphorylation was also investigated. Central nervous system opioid tolerance is associated with the reciprocal phosphorylation (regulation) of two PLCbeta isoforms, PLCbeta1 and PLCbeta3. However, although chelerythrine reinstates the chronic morphine-induced loss of the multiplicative VIP-DPDPE interaction, it does not alter the associated changes in PLCbeta phosphorylation, possibly indicating different time courses of restitution of function and/or involvement of different kinases for different components of tolerance. These results could provide a mechanistic rubric for understanding positive modulation of opioid antinociception by afferent transmission.
authors.affiliation: Department of Biochemistry, State University of New York, Downstate Medical Center, 450 Clarkson Ave., Box 8, Brooklyn, NY 11203, USA.
authors.forename: Nai-Jiang
authors.initials: NJ
authors.lastname: Liu
authors.forename: Sumita
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Alan R
authors.initials: AR
authors.lastname: Gintzler
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology*; D000242:Cyclic AMP / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D010716:Phosphatidylinositols / Q000378:metabolism; D054799:Phospholipase C beta; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology; D010738:Type C Phospholipases / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*; D017833:Visceral Afferents / Q000187:drug effects / Q000201:enzymology
chemical_list: D000701:Analgesics, Opioid; D007527:Isoenzymes; D010716:Phosphatidylinositols; D020033:Protein Isoforms; D017465:Receptors, Opioid, delta; D014660:Vasoactive Intestinal Peptide; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D011493:Protein Kinase C; D010738:Type C Phospholipases; D054799:Phospholipase C beta