The Effect of Minocycline on the Masticatory Movements following the Inferior Alveolar Nerve Transection in Freely Moving Rats

Ando

et al. 2017

IJMS

Self Cite

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.

Section: Alteration Of Orofacial Motor Activity In Neuropathic Paimentioning

confidence: 99%

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

Ando

et al. 2017

IJMS

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Kamimura

Journal of Oral Science

et al. 2018

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Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and C1-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain.

“…Recently, in a study, we observed that a selective MAGL inhibitor, JZL184, reduced NOP induced by injury to a branch of the trigeminal nerve in mice [258]. Trigeminal nerve injury was observed to induce neuropathic pain symptoms in the orofacial area [258,[263][264][265]. Systemic administration of the compound attenuated mechanical allodynia 2 h after administration [258].…”

Section: Route Of Administrationmentioning

confidence: 99%

“…Along with neurons, microglia may contribute to the synthesis and degradation of endocannabinoids [176,178,270]. Upregulated microglial cells in the brainstem trigeminal nuclei have been observed under NOP conditions to release pro-inflammatory mediators and contribute to the development of sensitization of brainstem neurons [113,179,263,264]. Activation of cannabinoid receptors in microglial cells by 2-AG may reduce the release of pro-inflammatory mediators.…”

Section: Route Of Administrationmentioning

confidence: 99%

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

Ando

2020

IJMS

Self Cite

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.