Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation

Abstract

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g. corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an Nmethyl-D-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.

Clinical characteristics of pain in patients with pituitary adenomas

“…We found that CD patients are more prone to develop pain, which is not surprising, since hypothalamo-pituitary-adrenal axis dysfunction has been suggested as a contributing factor to the development of chronic pain both in animal models and clinical studies (6). Recent studies have identified cortisol as a positive predictor of pain sensitivity (28).…”

“…In acromegaly, GH excess leads to persisting joint-related complaints such as arthropathy and arthralgia (5). On the other hand, both animal models and clinical studies have documented hypothalamo-pituitary-adrenal axis dysfunction as a potential contributing factor to the development of chronic pain via stress mechanisms, allowing potential association with a hypercortisolaemic state in CD (6). However, this has not been systemically investigated so far.…”

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

“…Even though it is unclear how NMDAR1-AB are generated by chronic stress, it should be considered that NMDAR1 are not only expressed in the brain but also by peripheral organs and tissues, including adrenal glands and gut [47] which may be involved in triggering NMDAR1-AB formation but may also be functionally modulated by them. Since NMDAR antagonists are increasingly recognized as antidepressant, anxiolytic, and anti-inflammatory agents [48][49][50][51][52], we speculate that stress-induced NMDAR1-AB could serve as endogenous stress protectants. Remarkably, also in stroke, NMDAR1-AB can be protective [8].…”

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…Similarly, intrathecal dosing of an MR antagonist, spironolactone (SPIRO) or eplerenone, also reversed the allodynic responses (Gu et al, 2011;Dong et al, 2012). Additional studies have provided evidence for antinociceptive mechanisms that involve NMDA and possibly opiate receptor modulation by GR (Wang et al, 2005;Dong et al, 2006;Alexander et al, 2009) and modulation of spinal microglia activity by MR (Sun et al, 2012). In addition to the spinal site of action, targeting GR or MR within the central nucleus of the amygdala (CeA) with agonists (CORT/ dexamethasone or aldosterone) or antagonists (MIFE/SPIRO) can also induce or inhibit somatic allodynia and colonic hypersensitivity to colorectal distension Greenwood-Van Meerveld, 2007, 2010).…”