title: Exposure to Gulf War Illness chemicals induces functional muscarinic receptor maladaptations in muscle nociceptors.
abstract: Chronic pain is a component of the multisymptom disease known as Gulf War Illness (GWI). There is evidence that pain symptoms could have been a consequence of prolonged and/or excessive exposure to anticholinesterases and other GW chemicals. We previously reported that rats exposed, for 8 weeks, to a mixture of anticholinesterases (pyridostigmine bromide, chlorpyrifos) and a Nav (voltage activated Na(+) channel) deactivation-inhibiting pyrethroid, permethrin, exhibited a behavior pattern that was consistent with a delayed myalgia. This myalgia-like behavior was accompanied by persistent changes to Kv (voltage activated K(+)) channel physiology in muscle nociceptors (Kv7, KDR). In the present study, we examined how exposure to the above agents altered the reactivity of Kv channels to a muscarinic receptor (mAChR) agonist (oxotremorine-M). Comparisons between muscle nociceptors harvested from vehicle and GW chemical-exposed rats revealed that mAChR suppression of Kv7 activity was enhanced in exposed rats. Yet in these same muscle nociceptors, a Stromatoxin-insensitive component of the KDR (voltage activated delayed rectifier K(+) channel) exhibited decreased sensitivity to activation of mAChR. We have previously shown that a unique mAChR-induced depolarization and burst discharge (MDBD) was exaggerated in muscle nociceptors of rats exposed to GW chemicals. We now provide evidence that both muscle and vascular nociceptors of naïve rats exhibit MDBD. Examination of the molecular basis of the MDBD in naïve animals revealed that while the mAChR depolarization was independent of Kv7, the action potential burst was modulated by Kv7 status. mAChR depolarizations were shown to be dependent, in part, on TRPA1. We argue that dysfunction of the MDBD could be a functional convergence point for maladapted ion channels and receptors consequent to exposure to GW chemicals.
authors.affiliation: Division of Neuroscience, Dept. of Oral and Maxillofacial Surgery, Box 100416, JHMHC, University of Florida College of Dentistry, Gainesville, FL 32610, USA. Electronic address: bcooper@dental.ufl.edu.
authors.forename: B Y
authors.initials: BY
authors.lastname: Cooper
authors.affiliation: Dept. of Physiological Sciences, University of Florida College of Veterinary Science, Gainesville, FL 32610, USA. Electronic address: rdjohnso@ufl.edu.
authors.forename: R D
authors.initials: RD
authors.lastname: Johnson
authors.affiliation: Division of Neuroscience, Dept. of Oral and Maxillofacial Surgery, Box 100416, JHMHC, University of Florida College of Dentistry, Gainesville, FL 32610, USA. Electronic address: tnutter@dental.ufl.edu.
authors.forename: T J
authors.initials: TJ
authors.lastname: Nutter
mesh_terms: D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004390:Chlorpyrifos; D059350:Chronic Pain / Q000139:chemically induced* / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D026023:Permethrin; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011729:Pyridostigmine Bromide; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D002619:Chemical Warfare Agents; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D026023:Permethrin; D004390:Chlorpyrifos; D011729:Pyridostigmine Bromide
keywords: ADP; Chlorpyrifos; Gulf War Syndrome; K(v)7; Muscarinic; Nociceptor