Morphine inhibits acid-sensing ion channel currents in rat dorsal root ganglion neurons.
Extracellular acidosis is a common feature in pain-generating pathological conditions. Acid-sensing ion channels (ASICs), pH sensors, are distributed in peripheral sensory neurons and participate in nociception. Morphine exerts potent analgesic effects through the activation of opioid receptors for various pain conditions. A cross-talk between ASICs and opioid receptors in peripheral sensory neurons has not been shown so far. Here, we have found that morphine inhibits the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Morphine dose-dependently inhibited proton-gated currents mediated by ASICs in the presence of the TRPV1 inhibitor capsazepine. Morphine shifted the proton concentration-response curve downwards, with a decrease of 51.4±3.8% in the maximum current response but with no significant change in the pH0.5 value. Another μ-opioid receptor agonist DAMGO induced a similar decrease in ASIC currents compared with morphine. The morphine inhibition of ASIC currents was blocked by naloxone, a specific opioid receptor antagonist. Pretreatment of forskolin, an adenylyl cyclase activator, or the addition of cAMP reversed the inhibitory effect of morphine. Moreover, morphine altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, peripheral applied morphine relieved pain evoked by intraplantar of acetic acid in rats. Our results indicate that morphine can inhibit the activity of ASICs via μ-opioid receptor and cAMP dependent signal pathway. These observations demonstrate a cross-talk between ASICs and opioid receptors in peripheral sensory neurons, which was a novel analgesic mechanism of morphine.
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China; Neurology Department, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, PR China.
Qi
Q
Cai
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China.
Chun-Yu
CY
Qiu
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China.
Fang
F
Qiu
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China.
Ting-Ting
TT
Liu
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China.
Zu-Wei
ZW
Qu
Neurology Department, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, PR China. Electronic address: lym9381@126.com.
Yu-Min
YM
Liu
Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning 437100, Hubei, PR China. Electronic address: wangping_hu@163.com.
Wang-Ping
WP
Hu
D019342:Acetic Acid; D062646:Acid Sensing Ion Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011522:Protons; D017450:Receptors, Opioid, mu; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D009020:Morphine; C071423:capsazepine; D019342:Acetic Acid; D002211:Capsaicin
Acid-sensing ion channel; Dorsal root ganglion neuron; Electrophysiology; Morphine; Opioid receptor; Pain; Proton-gated current