title: Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord.
abstract: In both the spared nerve injury (SNI) and spinal nerve ligation (SNL) rat peripheral neuropathic pain models the presynaptic inhibitory effect of the mu opioid receptor (MOR) agonist (DAMGO) on primary afferent-evoked excitatory postsynaptic currents (EPSCs) and miniature EPSCs in superficial dorsal horn neurons is substantially reduced, but only in those spinal cord segments innervated by injured primary afferents. The two nerve injury models also reduce the postsynaptic potassium channel opening action of DAMGO on lamina II spinal cord neurons, but again only in segments receiving injured afferent input. The inhibitory action of DAMGO on ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons is also reduced in affected segments following nerve injury. MOR expression decreases substantially in injured dorsal root ganglion neurons (DRG), while intact neighboring DRGs are unaffected. Decreased activation of MOR on injured primary afferent central terminals and the second order neurons they innervate may minimize any reduction by opioids of the spontaneous pain mediated by ectopic input from axotomized small diameter afferents. Retention of MOR expression and activity in nearby non-injured afferents will enable, however, an opioid-mediated reduction of stimulus-evoked and spontaneous pain carried by intact nociceptor afferents and we find that intrathecal DAMGO (1000 ng) reduces mechanical hypersensitivity in rats with SNL. Axotomy-induced changes in MOR may contribute to opioid- insensitive components of neuropathic pain while the absence of these changes in intact afferents may contribute to the opioid sensitive components.
authors.affiliation: Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, Boston, MA 02129, USA.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kohno
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Nobuko
authors.initials: N
authors.lastname: Ito
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Allchorne
authors.forename: Katia
authors.initials: K
authors.lastname: Befort
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Karchewski
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004789:Enzyme Activation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007839:Functional Laterality; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D016900:Neurofilament Proteins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051774:neurofilament protein H; D048049:Extracellular Signal-Regulated MAP Kinases