Pain Intensity and Duration Can Be Enhanced by Prior Challenge: Initial Evidence Suggestive of a Role of Microglial Priming

Abstract

Activation of spinal microglia and consequent release of pro-inflammatory mediators facilitate pain. Under certain conditions, responses of activated microglia can become enhanced. Enhanced microglial production of pro-inflammatory products may result from priming (sensitization), similar to macrophage priming. We hypothesized that if spinal microglia were primed by an initial inflammatory challenge, subsequent challenges may create enhanced pain. Here, we used a "twohit" paradigm using two successive challenges, which affect overlapping populations of spinal microglia, presented two weeks apart. Mechanical allodynia and/or activation of spinal glia were assessed. Initially, laparotomy preceded systemic lipopolysaccharide (LPS). Prior laparotomy caused prolonged microglial (not astrocyte) activation plus enhanced LPS-induced allodynia. In this "twohit" paradigm, minocycline, a microglial activation inhibitor, significantly reduced later exaggerated pain induced by prior surgery when minocycline was administered intrathecally for 5 days starting either at the time of surgery or 5 days before LPS administration. To test generality of the priming effect, subcutaneous formalin preceded intrathecal HIV-1 gp120, which activates spinal microglia and causes robust allodynia. Prior formalin enhanced intrathecal gp120-induced allodynia, suggesting that microglial priming is not limited to laparotomy and again supporting a spinal site of action. Therefore, spinal microglial priming may increase vulnerability to pain enhancement.

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

“…This process was dependent upon dorsal spinal microglial reactivity and NLRP3 inflammasomes. These findings comport with prior demonstrations that repeated immune challenges induce a transition from acute to chronic pain (60,67,68), which may also underpin pain comorbidities (69)(70)(71). An evaluation of the longterm consequences of opioid treatment for chronic pain will identify whether this phenomenon manifests clinically.…”

“…Finally, the implications of the present studies may extend beyond opioids as the second hit. A broad range of repeated neuroinflammatory challenges not only induce a transition from acute to persistent pain (60,67,68), but also induce behaviors that are comorbid with pain, including cognitive impairment (69), depression (70), and anxiety (71). Therefore, our data provide a rationale to examine whether the ubiquitous management of chronic pain with opioids contributes to the incidence of such pain, and potentially pain comorbidities-a hypothesis not previously considered or tested.…”

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

“…After a stimulus has resolved, experimental evidence suggests microglia remain "primed", entering a sensitised state in which they do not actively produce pro-inflammatory substances, yet they over-respond to subsequent stimuli, increasing pro-inflammatory cytokine release and exaggerating pain. [94][95][96] Activation of spinal microglia and astrocytes has been demonstrated in virtually every clinically relevant animal model of an enhanced pain state 88 with similar results reported for trigeminal pain models. 97 Moreover, glial-attenuating pharmacological interventions are able to block the phenotypic transformation of glial cells into the activated state and prevent both allodynia and hyperalgesia across a diverse range of pre-clinical pathological pain models.…”

Negative affectivity predicts decreased pain tolerance during low-grade inflammation in healthy women

“…These models identified as key mechanism the activation of glia cells by inflammatory mediators, which in turn alter neuronal functioning along the pain pathway (Hains et al, 2010;Watkins et al, 2007). Recently a mechanism was proposed by Frank et al (2013) to explain how stress acts on central immune regulation, based on data showing that stress-related increases of glucocorticoids (which typically have an anti-inflammatory effect) can also enhance inflammatory responses to stressors, probably by sensitization of glia cells (Frank et al, 2013).…”