Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence.
Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced μ-opioid receptor (MOR) constitutive activity (MOR(CA)) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3',5'-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MOR(CA) initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR(CA) suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
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Corder
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Doolen
R R
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Donahue
M K
MK
Winter
B L
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Jutras
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He
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Hu
J S
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Wieskopf
J S
JS
Mogil
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Storm
Z J
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Wang
K E
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McCarson
B K
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Taylor
D059787:Acute Pain / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D059350:Chronic Pain / Q000378:metabolism*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D059226:Nociceptive Pain / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D000249:Adenosine Monophosphate; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D005620:Freund's Adjuvant; D007530:Isoflurane; D000262:Adenylyl Cyclases