title: Loss of functional neuronal nicotinic receptors in dorsal root ganglion neurons in a rat model of neuropathic pain.
abstract: Recent evidence has suggested that the anti-allodynic effect of neuronal acetylcholine receptor (nAChR) agonists may have a peripheral component [L.E. Rueter, K.L. Kohlhaas, P. Curzon, C.S. Surowy, M.D. Meyer, Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain, Pain 103 (2003) 269-276]. In further studies of the peripheral anti-allodynic mechanisms of nAChR agonists, we investigated the function of nAChRs in acutely isolated dorsal root ganglion (DRG) neurons from allodynic [L5-L6 spinal nerve ligation (SNL)] and naive adult rats. Following determination of cell diameter and membrane capacitance, responses to rapid applications of nAChR agonists were recorded under whole cell patch clamp. nAChR inward currents were observed in approximately 60% of naive neurons, across small, medium, and large diameter cells. Evoked nAChR currents could be clustered into three broad classes: fast transient, biphasic, and slow desensitizing currents, consistent with multiple subtypes of nAChR expressed in DRG [J.R. Genzen, W. Van Cleve, D.S. McGehee, Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes, J. Neurophysiol. 86 (2001) 1773-1782]. In contrast, in neurons from allodynic animals, the occurrence and amplitude of responses to nAChR agonists were significantly reduced. Reduced responsiveness to nAChR agonists covered the range of DRG neuron sizes. The decrease in the responsiveness to nAChR agonists was not seen in neighboring uninjured L4 neurons. The significant decrease in the number of cells with nAChR agonist responses, compounded with the significant decrease in response amplitude, indicates that there is a marked down regulation of functional nAChRs in DRG somata associated with SNL.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9/1125, 100 Abbott Park Rd., Abbott Park, IL 60064-6118, USA. gilles.dube@abbott.com
authors.forename: Gilles R
authors.initials: GR
authors.lastname: Dubé
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000473:pathology*; D008026:Ligation / Q000379:methods; D008161:Lumbosacral Region; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000145:classification / Q000502:physiology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010146:Pain / Q000473:pathology* / Q000503:physiopathology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology
chemical_list: C104288:A 85380; D001384:Azetidines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D000109:Acetylcholine