Behavioral, cellular and molecular maladaptations covary with exposure to pyridostigmine bromide in a rat model of gulf war illness pain

Toxicol Appl Pharmacol. 2018 Aug 1;352:119-131. doi: 10.1016/j.taap.2018.05.023. Epub 2018 May 24.


Many veterans of Operation Desert Storm (ODS) struggle with the chronic pain of Gulf War Illness (GWI). Exposure to insecticides and pyridostigmine bromide (PB) have been implicated in the etiology of this multisymptom disease. We examined the influence of 3 (DEET (N,N-diethyl-meta-toluamide), permethrin, chlorpyrifos) or 4 GW agents (DEET, permethrin, chlorpyrifos, pyridostigmine bromide (PB)) on the post-exposure ambulatory and resting behaviors of rats. In three independent studies, rats that were exposed to all 4 agents consistently developed both immediate and delayed ambulatory deficits that persisted at least 16 weeks after exposures had ceased. Rats exposed to a 3 agent protocol (PB excluded) did not develop any ambulatory deficits. Cellular and molecular studies on nociceptors harvested from 16WP (weeks post-exposure) rats indicated that vascular nociceptor Nav1.9 mediated currents were chronically potentiated following the 4 agent protocol but not following the 3 agent protocol. Muscarinic linkages to muscle nociceptor TRPA1 were also potentiated in the 4 agent but not the 3 agent, PB excluded, protocol. Although Kv7 activity changes diverged from the behavioral data, a Kv7 opener, retigabine, transiently reversed ambulation deficits. We concluded that PB played a critical role in the development of pain-like signs in a GWI rat model and that shifts in Nav1.9 and TRPA1 activity were critical to the expression of these pain behaviors.

Keywords: Chronic Pain; Gulf War Illness; Muscarinic; Na(v)1.9; Pyridostigmine; TRPA1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Behavior, Animal*
  • Chlorpyrifos
  • DEET
  • Disease Models, Animal
  • Ganglia, Spinal / metabolism*
  • Ganglia, Spinal / physiopathology
  • KCNQ Potassium Channels / metabolism
  • Male
  • Muscle, Skeletal / innervation*
  • NAV1.9 Voltage-Gated Sodium Channel / metabolism*
  • Pain Perception*
  • Pain Threshold
  • Permethrin
  • Persian Gulf Syndrome / chemically induced
  • Persian Gulf Syndrome / metabolism*
  • Persian Gulf Syndrome / physiopathology
  • Persian Gulf Syndrome / psychology*
  • Pyridostigmine Bromide*
  • Rats, Sprague-Dawley
  • Receptors, Muscarinic / metabolism
  • Signal Transduction
  • TRPA1 Cation Channel / metabolism*
  • Time Factors


  • KCNQ Potassium Channels
  • NAV1.9 Voltage-Gated Sodium Channel
  • Receptors, Muscarinic
  • Scn11a protein, rat
  • TRPA1 Cation Channel
  • Trpa1 protein, rat
  • DEET
  • Permethrin
  • Chlorpyrifos
  • Pyridostigmine Bromide