DEET potentiates the development and persistence of anticholinesterase dependent chronic pain signs in a rat model of Gulf War Illness pain

Abstract

Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted to assess the influence of acute DEET (10-100μM) on muscle and vascular nociceptor K7, K, Na1.8 and Na1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5-12weeks post-exposure and persisted through weeks 21-24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor K7, K, Na1.8 or Na1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of K7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role.

Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness

“…Furthermore, the observed outcomes are similar to those reported in other rodent models of GWI at the chronic post-exposure time points, which use oral and the topical routes [44]. As such, the chronic effects of GW agent exposure appear to be unaffected by the mode of delivery [44–46,74]. …”

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

“…During the 1991 Gulf War, soldiers had the potential to be exposed to all three of these categories of AChEIs: the pesticides chlorpyrifos (CPF) and dichlorvos (DDVP) were regularly and pervasively used for pest control, pyridostigmine bromide (PB) was prescribed to be taken every 8 h as a prophylactic against potential nerve agent exposure, and the demolition of ammunition storage facilities released sarin and cyclosarin nerve agents and potentially exposed veterans to these chemical weapons ( Tuovinen et al, 1999 ; Institute of Medicine (US) Committee on Health Effects Associated with Exposures During the Gulf War, 2000 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; White et al, 2016 ). Exposure to AChEIs has been repeatedly implicated as the potential cause of Gulf War Illness (GWI), a chronic multi-symptom disorder affecting nearly one-third of the veterans that returned from the 1991 conflict, by both epidemiological ( Sullivan et al, 2003 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; Steele et al, 2012 ; Kerr, 2015 ; White et al, 2016 ; Sullivan et al, 2018 ) and preclinical studies ( Henderson et al, 2001 ; Amourette et al, 2009 ; Lamproglou et al, 2009 ; Abdullah et al, 2012 ; Abdullah et al, 2013 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Ojo et al, 2014 ; Nutter et al, 2015 ; O’Callaghan et al, 2015 ; Zakirova et al, 2015 ; Abdullah et al, 2016 ; Cooper et al, 2016 ; Phillips and Deshpande, 2016 ; Pierce et al, 2016 ; Alhasson et al, 2017 ; Emmerich et al, 2017 ; Flunker et al, 2017 ; Locker et al, 2017 ; Shetty et al, 2017 ; Zakirova et al, 2017 ; Ashbrook et al, 2018 ; Carreras et al, 2018 ; Cooper et al, 2018 ; Koo et al, 2018 ; Macht et al, 2018 ; Miller et al, 2018 ; Phillips and Deshpande, 2018 ; Seth et al, 2018 ; Macht et al, 2019 ; Michalovicz et al, 2019 ). Acute exposure to toxic levels of AChEIs, particularly the organophosphate (OP) compounds like the pesticides and nerve agents, has a number of systemic effects (i.e.…”

Environmental Exposure History and Vulvodynia Risk: A Population-Based Study

“…has been reported to be associated with lower cognitive performance, Parkinson's disease, Alzheimer's disease, 13,14 polyneuropathies, affective disorders, and suicide attempts, 4 as well as with delayed pain in studies on rats. 6 The possibility that the environmental exposures assessed here as well as other, less studied, environmental exposures 5 may have an impact on the risk not only of vulvodynia but also of other chronic pain disorders or affective disorders associated with vulvodynia 3,15-17 demands further study. The route by which environmental exposures impact vulvodynia risk may be singular or multiple, and may impact mechanisms that have been previously reported to differ among women with vulvodynia than among those without this disorder.…”

“…Of the 1585 eligible women, 20.5% (N = 325) were defined as cases, of whom 171 (52.6%) met criteria for vulvodynia at baseline and 154 (47.4%) met criteria on a subsequent survey (6,12,18, or 24 months). Nineteen percent (N = 301) were defined as having intermediate symptoms, and 60.5% (N = 959) were defined as being asymptomatic.…”

“…Yet, the etiology of this pain disorder continues to be elusive. Environmental exposure to chemicals has been associated with neurologic disorders 4 as well as with acute and chronic pain in animals, [5][6][7] including other human populations. 8 Elucidating risk factors for acute and chronic pain is the focus of this substantial study, but to date the role of environmental exposures in susceptibility to vulvodynia has not been examined.…”