Hydrogen sulfide inhibits opioid withdrawal-induced pain sensitization in rats by down-regulation of spinal calcitonin gene-related peptide expression in the spine.
Hyperalgesia often occurs in opioid-induced withdrawal syndrome. In the present study, we found that three hourly injections of DAMGO (a μ-opioid receptor agonist) followed by naloxone administration at the fourth hour significantly decreased rat paw nociceptive threshold, indicating the induction of withdrawal hyperalgesia. Application of NaHS (a hydrogen sulfide donor) together with each injection of DAMGO attenuated naloxone-precipitated withdrawal hyperalgesia. RT-PCR and Western blot analysis showed that NaHS significantly reversed the gene and protein expression of up-regulated spinal calcitonin gene-related peptide (CGRP) in naloxone-treated animals. NaHS also inhibited naloxone-induced cAMP rebound and cAMP response element-binding protein (CREB) phosphorylation in rat spinal cord. In SH-SY5Y neuronal cells, NaHS inhibited forskolin-stimulated cAMP production and adenylate cyclase (AC) activity. Moreover, NaHS pre-treatment suppressed naloxone-stimulated activation of protein kinase C (PKC) α, Raf-1, and extracellular signal-regulated kinase (ERK) 1/2 in rat spinal cord. Our data suggest that H2S prevents the development of opioid withdrawal-induced hyperalgesia via suppression of synthesis of CGRP in spine through inhibition of AC/cAMP and PKC/Raf-1/ERK pathways.
Department of Pharmacology,Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
Hai-Yu
HY
Yang
Department of Pharmacology,Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
Zhi-Yuan
ZY
Wu
Department of Pharmacology,Yong Loo Lin School of Medicine, National University of Singapore,Singapore.
Jin-Song
JS
Bian
D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009270:Naloxone / Q000009:adverse effects; D009447:Neuroblastoma / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013131:Spine / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000150:complications / Q000209:etiology*
D000701:Analgesics, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D050882:CREB-Binding Protein; D000262:Adenylyl Cyclases; D015740:Calcitonin Gene-Related Peptide; D006862:Hydrogen Sulfide