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. 2010 Oct;11(10):1004-14.
doi: 10.1016/j.jpain.2010.01.271.

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

Leah E Hains  1 , Lisa C Loram, Julie L Weiseler, Matthew G Frank, Erik B Bloss, Paige Sholar, Frederick R Taylor, Jacqueline A Harrison, Thomas J Martin, James C Eisenach, Steven F Maier, Linda R Watkins
Affiliations

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

Leah E Hains et al. J Pain. 2010 Oct.

Abstract

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.

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Figures

Figure 1
Figure 1
Effect of laparotomy on the behavioral responses to mechanical stimuli following LPS (20 µg/kg, i.p.) administered two wk later (Panel A). LPS causes decreased withdrawal thresholds to mechanical stimuli only when preceded by laparotomy. Animals underwent laparotomy or sham surgery two wk before testing. Low-threshold mechanical sensitivity was assessed by the von Frey test before LPS (20 µg/kg) or vehicle injection (BL) and 30-480 min, 1 and 7 d after injection. Although laparotomy alone (laparotomy + vehicle; black circles) does not affect withdrawal thresholds, when paired with LPS, mechanical allodynia results (laparotomy + LPS; black squares), this is in contrast to the sham group, where LPS had no effect on behavior (sham + LPS; white squares). Values represent average thresholds for the left and right paws (means ± SEM). Panel B shows a significant difference in microglial activation in L4-5 dorsal horn two wk following laparotomy (black bar) compared to sham-operated controls (white bar).
Figure 2
Figure 2
Microglial activation in lumbosacral spinal cord after LPS administered two wk following laparotomy. Laparotomy (black bars) significantly increased OX-42 labeling in L3 a) and L4-L5 b). Systemic LPS induced an increase in OX-42 labeling in L4- L5 that was specific to sham-operated animals. In all areas examined, OX-42 activation was greater in laparotomy + vehicle animals compared to sham + vehicle controls. There was no interaction between laparotomy and LPS. Data represent mean integrated densities of OX-42 immunoreactivity ± SEM. *P < 0.05, **P < 0.05 vs. sham + vehicle; #P < 0.05 vs. sham + vehicle.
Figure 3
Figure 3
Representative images depicting OX-42 immunoreactivity in L4-L5 dorsal horn following LPS (20µg/kg i.p.) administered two wk after laparotomy. a) sham + vehicle, b) laparotomy + vehicle, c) sham + LPS and d) laparotomy + LPS. Scale bars represent 200 µm.
Figure 4
Figure 4
Effect of five-day minocycline administration (twice daily, or once daily, 90 µg, i.t.) or vehicle on a two-challenge paradigm of laparotomy and low dose, systemic LPS. (A) Minocycline administration began at the time of surgery (laparotomy + minocycline +LPS; black circles). (B) Minocycline administration beginning five days before LPS administration, with the last dose 1 h before LPS administration (laparotomy + minocycline +LPS; black circles). Two wk after laparotomy, LPS was administered intraperitoneally. Minocycline significantly reduced the duration of LPS-induced allodynia but not the intensity compared to rats treated with intrathecal vehicle (laparotomy + vehicle +LPS; open circles, P<0.001), irrespective of the dosing regimen. Data are presented as mean ± SEM. Values represent average thresholds for the left and right paws. *P < 0.01 at each respective time point for minocycline against vehicle.
Figure 5
Figure 5
Effect of intraplantar formalin on i.t. gp120-induced mechanical allodynia tested two wk later. Injection of formalin enhances gp120-induced mechanical allodynia tested two wk later. Formalin (5%) or vehicle was injected into the dorsal aspect of the right hindpaw two wk prior to testing on the plantar aspect of the hindpaw. The von Frey test was used to assess low-threshold mechanical allodynia before (BL), 20 and 60 min after i.t. administration of gp120 (1.5 µg) or vehicle. I.t. gp120 causes allodynia within 20 min of injection. Allodynia is greater in animals injected with formalin (black squares) two wk earlier compared to the vehicle + gp120 group (white squares). Values represent average thresholds of left and right hindpaws (means ± SEM). *P < 0.05 compared to all other groups.
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References

    1. Aley KO, Messing RO, Mochly-Rosen D, Levine JD. Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci. 2000;20:4680–4685. - PMC - PubMed
    1. Barrientos RM, Sprunger DB, Campeau S, Higgins EA, Watkins LR, Rudy JW, Maier SF. Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience. 2003;121:847–853. - PubMed
    1. Boisse L, Spencer SJ, Mouihate A, Vergnolle N, Pittman QJ. Neonatal immune challenge alters nociception in the adult rat. Pain. 2005;119:133–141. - PubMed
    1. Bruce J, Drury N, Poobalan AS, Jeffrey RR, Smith WC, Chambers WA. The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study. Pain. 2003;104:265–273. - PubMed
    1. Cadet R, Aigouy L, Woda A. Enhanced nociceptive behaviour following conditioning injection of formalin in the perioral area of the rat. Brain Res. 1995;676:189–195. - PubMed

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