Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators

Abstract

Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms underlying migraine. Migraine facial allodynia is modeled by applying inflammatory soup (histamine, bradykinin, serotonin, prostaglandin E2) over the dura. Whether glial and/or immune activation contributes to such pain is unknown. Here we tested if trigeminal nucleus caudalis (Sp5C) glial and/or immune cells are activated following supradural inflammatory soup, and if putative glial/immune inhibitors suppress the consequent facial allodynia. Inflammatory soup was administered via bilateral indwelling supradural catheters in freely moving rats, inducing robust and reliable facial allodynia. Gene expression for microglial/macrophage activation markers, interleukin-1β, and tumor necrosis factor-α increased following inflammatory soup along with robust expression of facial allodynia. This provided the basis for pursuing studies of the behavioral effects of 3 diverse immunomodulatory drugs on facial allodynia. Pretreatment with either of two compounds broadly used as putative glial/immune inhibitors (minocycline, ibudilast) prevented the development of facial allodynia, as did treatment after supradural inflammatory soup but prior to the expression of facial allodynia. Lastly, the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone likewise blocked development of facial allodynia after supradural inflammatory soup. Taken together, these exploratory data support that activated glia and/or immune cells may drive the development of facial allodynia in response to supradural inflammatory soup in unanesthetized male rats.

Keywords: Dura; Headache; Interleukin-1; Migraine; OX42; Tumor necrosis factor alpha.

Copyright © 2017 Elsevier B.V. All rights reserved.

Figures

Fig. 1

Supradural inflammatory soup induces facial allodynia and increases gene expression for proinflammatory mediators compared to supradural saline, A) facial allodynia, B) complement 3b receptor (CD11b), C) IL-1beta (IL-1), and D) TNF-α (n = 5–6 per group; p < 0.05).

Fig. 2

Minocycline suppresses supradural inflammatory soup induced facial allodynia when administered 15 min prior to the first injection (A, time course of facial allodynia; B, AUC on which statistics were performed) and 30 min after the second injection (C, time course of facial allodynia; D, AUC on which statistics were performed). (n = 6–8 per group; left and right data were averaged; *p < 0.05; AUC, area under the curve).

Fig. 3

Ibudilast suppresses supradural inflammatory soup induced facial allodynia when administered 15 min prior to the first injection (A, time course of facial allodynia; B, AUC on which statistics were performed) and 30 min after the second injection (C, time course of facial allodynia; D, AUC on which statistics were performed). (n = 6–8 per group; left and right data were averaged; *p < 0.05; AUC, area under the curve).

Fig. 4

The non-opioid toll-like receptor 4 antagonist (+)-Naltrexone suppresses supradural inflammatory soup induced facial allodynia when administered 2 h after to the second injection of inflammatory soup (A, time course of facial allodynia; B, AUC on which statistics were performed). (n = 6–8 per group; left and right data were averaged; *p < 0.05; AUC, area under the curve).