Prior laparotomy or corticosterone potentiates lipopolysaccharide-induced fever and sickness behaviors.

Stimulating sensitized immune cells with a subsequent immune challenge results in potentiated pro-inflammatory responses translating into exacerbated sickness responses (i.e. fever, pain and lethargy). Both corticosterone (CORT) and laparotomy cause sensitization, leading to enhanced sickness-induced neuroinflammation or pain (respectively). However, it is unknown whether this sensitization affects all sickness behaviors and immune cell responses equally. We show that prior CORT and prior laparotomy potentiated LPS-induced fever but not lethargy. Prior CORT, like prior laparotomy, was able to potentiate sickness-induced pain. Release of nitric oxide (NO) from peritoneal macrophages stimulated ex vivo demonstrates that laparotomy, but not CORT sensitizes these cells.

Pain intensity and duration can be enhanced by prior challenge: initial evidence suggestive of a role of microglial priming.

UNLABELLED: Activation of spinal microglia and consequent release of proinflammatory mediators facilitate pain. Under certain conditions, responses of activated microglia can become enhanced. Enhanced microglial production of proinflammatory 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 "two-hit" paradigm using 2 successive challenges, which affect overlapping populations of spinal microglia, presented 2 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 "two-hit" 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. PERSPECTIVE: Spinal microglia may become "primed" (sensitized) following their activation by disparate forms of peripheral trauma/inflammation. As a result, such primed microglia may overrespond to subsequent challenges, thereby enhancing pain intensity and duration.