title: Hydrogen sulfide attenuates opioid dependence by suppression of adenylate cyclase/cAMP pathway.
abstract: OBJECTIVE
  The best-established mechanism of opioid dependence is the up-regulation of adenylate cyclase (AC)/cAMP pathway, which was reported to be negatively regulated by hydrogen sulfide (H2S), a novel endogenous neuromodulator. The present study was, therefore, designed to determine whether H2S is able to attenuate the development of opioid dependence via down-regulating AC/cAMP pathway.
  
  
  RESULTS
  We demonstrated that application of sodium hydrosulphide (NaHS) and GYY4137, two donors of H2S, significantly alleviated naloxone-induced robust withdrawal jumping (the most sensitive and reliable index of opioid physical dependence) in morphine-treated mice. Repeated treatment with NaHS inhibited the up-regulated protein expression of AC in the striatum of morphine-dependent mice. Furthermore, NaHS also attenuated morphine/naloxone-elevated mRNA levels of AC isoform 1 and 8, production of cAMP, and phosphorylation of cAMP response element-binding protein (CREB) in mice striatum. These effects were mimicked by the application of exogenous H2S or over-expression of cystathione-β-synthase, an H2S -producing enzyme, in SH-SY5Y neuronal cells on treatment with [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin, a selective μ-opioid receptor agonist. Blockade of extracellular-regulated protein kinase 1/2 (ERK1/2) with its specific inhibitor attenuated naloxone-induced CREB phosphorylation. Pretreatment with NaHS or stimulation of endogenous H2S production also significantly suppressed opioid withdrawal-induced ERK1/2 activation in mice striatum or SH-SY5Y cells.
  
  
  METHODS
  H2S treatment is important in prevention of the development of opioid dependence via suppression of cAMP pathway in both animal and cellular models.
  
  
  CONCLUSIONS
  Our data suggest a potential role of H2S in attenuating the development of opioid dependence, and the underlying mechanism is closely related to the inhibition of AC/cAMP pathway.
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Hai-Yu
authors.initials: HY
authors.lastname: Yang
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Wu
authors.forename: Mark
authors.initials: M
authors.lastname: Wood
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Bian
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence; D009270:Naloxone / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D017362:Cyclic AMP Response Element-Binding Protein; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D009020:Morphine; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000262:Adenylyl Cyclases; D006862:Hydrogen Sulfide