Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice

Abstract

The evolutionary advantages to the suppression of pain during a stressful event (stress-induced analgesia (SIA)) are obvious, yet the reasoning behind sex-differences in the expression of this pain reduction are not. The different ways in which males and females integrate physiological stress responses and descending pain inhibition are unclear. A potential supraspinal modulator of stress-induced analgesia is the central nucleus of the amygdala (CeA). This limbic brain region is involved in both the processing of stress and pain; the CeA is anatomically and molecularly linked to regions of the hypothalamic pituitary adrenal (HPA) axis and descending pain network. The CeA exhibits sex-based differences in response to stress and pain that may differentially induce SIA in males and females. Here, sex-based differences in behavioral and molecular indices of SIA were examined following noxious stimulation. Acute restraint stress in male and female mice was performed prior to intraplantar injections of formalin, a noxious inflammatory agent. Spontaneous pain-like behaviors were measured for 60 min following formalin injection and mechanical hypersensitivity was evaluated 120 and 180 min post-injection. Restraint stress altered formalin-induced spontaneous behaviors in male and female mice and formalin-induced mechanical hypersensitivity in male mice. To assess molecular indices of SIA, tissue samples from the CeA and blood samples were collected at the 180 min time point. Restraint stress prevented formalin-induced increases in extracellular signal regulated kinase 2 (ERK2) phosphorylation in the male CeA, but no changes associated with pERK2 were seen with formalin or restraint in females. Sex differences were also seen in plasma corticosterone concentrations 180 min post injection. These results demonstrate sex-based differences in behavioral, molecular, and hormonal indices of acute stress in mice that extend for 180 min after stress and noxious stimulation.

Nerve injury alters restraint-induced activation of the basolateral amygdala in male rats

“…Bilateral injections of retrograde tracer into the medial prefrontal cortex (mPFC) combined with the immunohistochemical detection of Fos family proteins revealed that amygdala neurons projecting to the mPFC were not immunoreactive for either cFos or FosB/∆FosB suggesting that this speci c pathway is not activated by either acute restraint, CCI, or a combination of these stimuli. Our experiments were carried out exclusively in male rats, we are aware however that there is evidence for sex differences in the role of the amygdala in mediating changes in pain sensitivity as a result of chronic stress (Long et al, 2016), whether our ndings of the effects of neuropathic injury on amygdala responses to acute stressors is also seen in female rats will be important to determine as there are many more females with chronic pain than males (Mogil, 2020).…”

Ipsi- and Contralateral Moxibustion Generate Similar Analgesic Effect on Inflammatory Pain

“…As previously described [13], spontaneous behaviors following intraplantar formalin injection were measured. Mice were firstly acclimatized for 60 min in an individual Plexiglas cage placed atop a glass surface and then were videotaped following intradermal formalin injection and analyzed for nociceptive behaviors (defined as licking, lifting, and flinching of the injected paw, sum of licking/biting times were counted) in five min bins for 60 min following formalin injection.…”

Qualitative sex differences in pain processing: emerging evidence of a biased literature

“…The high-profile observation that κ-opioid receptor agonists produce analgesia in men but not women 110 -which engendered great interest in the subfield at its inception -was not replicated in a subsequent study using three experimental pain models 111 . However, two further examples of male-specific endogenous analgesia systems have recently been described, including a naloxone-sensitive system that suppresses orofacial pain in male mice 112 and a restraint stress inhibition of formalin pain in male mice involving the central amygdala 113 . Chronic pain has been shown to produce long-lasting changes in neuroanatomy 114 ; recent reports suggest that some of these changes might be dependent on sex.…”