Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

Abstract

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice

“…However, the effects of MAGL inhibitors on animal models of orofacial neuropathic pain have not been assessed. Injury to the trigeminal nerve in the orofacial area induced neuropathic pain in animal models (26)(27)(28)(29)(30). This type of nerve injury causes sensitization of the peripheral and central nervous systems (e.g., allodynia and hyperalgesia), which are typical characteristics of neuropathic pain (2,28,29).…”

“…Injury to the trigeminal nerve in the orofacial area induced neuropathic pain in animal models (26)(27)(28)(29)(30). This type of nerve injury causes sensitization of the peripheral and central nervous systems (e.g., allodynia and hyperalgesia), which are typical characteristics of neuropathic pain (2,28,29). Furthermore, use of the synthetic cannabinoid WIN 55,212-2 was recently reported to attenuate allodynia and hyperalgesia caused by chronic constriction injury of the infraorbital nerve (ION) (31).…”

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

“…CB2 receptors are also present in glial cells (e.g., microglia), which were observed to be upregulated following inflammation or nerve injury [109][110][111][112]. Microglia are important mediators for neuropathic pain development [113][114][115]. Various studies have reported that reactive microglia interact with neurons and contribute to the development of neuropathic pain [113][114][115].…”

“…Microglia are important mediators for neuropathic pain development [113][114][115]. Various studies have reported that reactive microglia interact with neurons and contribute to the development of neuropathic pain [113][114][115]. In different models of neuropathic pain such as peripheral nerve injury, chemotherapy-induced neuropathic pain and chronic post-ischemia pain, CB2 receptor expression is increased in microglia [110,116,117].…”

“…The recruitment of immune cells at the site of nerve injury/inflammation may provide a further source of endocannabinoid synthesis and metabolism [19,21,[173][174][175]. Endocannabinoids can be synthesized from reactive glial cells [176][177][178], which are observed to be increased under inflammatory and neuropathic pain conditions [113,179].…”