Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence
- 20 September 2013
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 341 (6152), 1394-1399
- https://doi.org/10.1126/science.1239403
Abstract
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 (MORCA) 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, MORCA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MORCA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.Keywords
This publication has 81 references indexed in Scilit:
- Negative Reinforcement Reveals Non-Evoked Ongoing Pain in Mice With Tissue or Nerve InjuryThe Journal of Pain, 2012
- Hyperalgesia by synaptic long-term potentiation (LTP): an updateCurrent Opinion in Pharmacology, 2011
- Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggersBrain, 2010
- N -Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory painPain, 2010
- Unmasking the tonic-aversive state in neuropathic painNature Neuroscience, 2009
- Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural PlasticityThe Journal of Pain, 2009
- Centralization of noxious stimulus-induced analgesia (NSIA) is related to activity at inhibitory synapses in the spinal cordPain, 2009
- Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insultPain, 2008
- Distinct Roles of Adenylyl Cyclases 1 and 8 in Opiate Dependence: Behavioral, Electrophysiological, and Molecular StudiesBiological Psychiatry, 2008
- Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addictionBritish Journal of Pharmacology, 2008