Exacerbated Headache-Related Pain in the Single Prolonged Stress Preclinical Model of Post-traumatic Stress Disorder

Yong Zhang,Kelly M Standifer

doi:10.1007/s10571-020-00962-8

Yong Zhang, Kelly M Standifer

Open Access

https://doi.org/10.1007/s10571-020-00962-8

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Abstract

Chronic headache pain is one of the most commonly reported comorbid pain conditions with post-traumatic stress disorder (PTSD) patients and resistant to effective treatment, yet no combined preclinical model of the two disorders has been reported. Here, we used a modified chronic headache pain model to investigate the contribution of single prolonged stress (SPS) model of PTSD with sodium nitroprusside (SNP)-induced hyperalgesia. Injection of SNP (2 mg/kg, i.p.) occurred every other day from day 7 to day 15 after initiation of SPS in rats. Paw withdrawal threshold (PWT) to von Frey stimuli and tail flick latencies (TFL) dramatically decreased as early as 7 days after SPS and lasted until at least day 21. Basal PWT and TFL also significantly decreased during the SNP treatment period. The lower nociceptive thresholds recovered in 6 days following the final SNP injection in SNP group, but not in SPS + SNP group. Elevated nociceptin/OFQ (N/OFQ) levels observed in cerebrospinal fluid of SPS rats were even higher in SPS + SNP group. Glial fibrillary acidic protein (GFAP) and N/OFQ peptide (NOP) receptor mRNA expression increased in dorsal root ganglia (DRG) 21 days after SPS exposure; mRNA increases in the SPS/SNP group was more pronounced than SPS or SNP alone. GFAP protein expression was upregulated in trigeminal ganglia by SPS. Our results indicate that traumatic stress exaggerated chronic SNP-induced nociceptive hypersensitivity, and that N/OFQ and activated satellite glia cells may play an important role in the interaction between both conditions.

Highlights

Estimates of past-year and lifetime prevalence of post-traumatic stress disorder (PTSD) are 4.7 and 6.1%, respectively, in the USA (Goldstein et al 2016); this rate is much higher in those with chronic pain
Glial fibrillary acidic protein (GFAP) and N/OFQ peptide (NOP) receptor mRNA expression increased in dorsal root ganglia (DRG) 21 days after Single prolonged stress (SPS) exposure; mRNA increases in the SPS/sodium nitroprusside (SNP) group was more pronounced than SPS or SNP alone
Since nitric oxide donors nitroglycerin and sodium nitroprusside (SNP) induce allodynia and hyperalgesia to thermal stimuli, the ability of SNP (Galeotti and Ghelardini 2013) to produce acute hyperalgesia in rats was tested using assessment methods utilized in the headache and in the SPS literature

Summary

Introduction

Estimates of past-year and lifetime prevalence of PTSD are 4.7 and 6.1%, respectively, in the USA (Goldstein et al 2016); this rate is much higher in those with chronic pain. The PTSD prevalence was 20.5%, 11.2%, and 0.3% among persons with chronic widespread pain, headache, and back pain, respectively (Siqveland et al 2017). The interaction of PTSD and chronic pain gained growing interest in last two decades; current knowledge relies almost entirely upon clinical observations; development of animal models of PTSD and chronic pain will help us better understand the underlying mechanisms contributing to this comorbidity. Single prolonged stress (SPS), an established animal model for PTSD, simulates many of the PTSD symptoms reported in humans such as exaggerated negative feedback of the HPA axis, hypocortisolism (Zhang et al 2012), enhanced fear and anxiety responses, and cognitive impairment (Yamamoto et al 2009; Lisieski et al 2018). NTG has been commonly used in rodent models of migraine wherein systemic administration of NTG produced acute hyperalgesia in rats (Tassorelli et al 2003) and mice

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