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.

Ibudilast Attenuates Folic Acid–Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways

“…Ibudilast, a nonselective phosphodiesterase 4 (PDE4) inhibitor and TLR4 antagonist, is clinically used to treat asthma (Kawasaki et al, 1992). Recently, ibudilast was reported to exert a protective effect on neuroinflammation, such as in Parkinson's disease, poststroke dizziness, and delirium, by downregulating TLR4 (Rolan et al, 2009;Zhaleh et al, 2014;Wieseler et al, 2017;Jalleh et al, 2012). Additionally, ibudilast alleviates the microglial cell-mediated inflammatory response caused by human immunodeficiency virus-1 by blocking the TLR4/NF-κB pathway (Kiebala and Maggirwar 2011).…”

Purines in Pain as a Gliopathy

“…Although several painful conditions are undoubtedly of neuronal origin, the existence of an altered bidirectional signaling between neurons and activated glial cells has brought to the definition of pain as a “gliopathy” ( Ji et al, 2013 ). In the central nervous system (CNS), neuronal excitability in pain pathways is enhanced by resident microglia, astrocytes, oligodendrocytes, and by infiltrating cells, such as T cells and macrophages, overall constituting the so-called “neuroimmune interface.” Following peripheral nerve damage, spinal cord microglia sense a variety of neuron-derived stimuli leading to their transition toward a reactive state ( Grace et al, 2014 ), whose inhibition through the antibiotic minocycline has proven anti-hyperalgesic and anti-allodynic ( Wieseler et al, 2017 ). Microglia activation is followed by immune cell recruitment and by the appearance of a neurotoxic astrocyte subpopulation, the so-called A1 astrocytes ( Liddelow et al, 2017 ).…”

The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders

“…Activation of TLR4 has been implicated in the pathogenesis of migraine 9,15 and (+)-Naltrexone blocked the development of facial allodynia in modeled migraine in rats. 9…”

“…Inhibiting the TLR4 with naltrexone in nerve cells of the dorsal root ganglia (DRG) and trigeminal ganglion led to reduction in pro-inflammatory cytokines' production and reversal of neuropathic pain and migraine in animal studies. [4][5][6][7][8][9][10] Naltrexone can prevent a "localized cytokine storm" (our term) in nerve cells averting pain. We postulate that naltrexone's toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines' production in the trigeminal ganglion averting "overactive nerves" and migraine.…”