Cells, Vol. 12, Pages 155: Preclinical Studies of Posttraumatic Headache and the Potential Therapeutics

Thus, it is promising that enhancement of eCBs by inhibition of the eCB catabolic enzymes or direct administration of eCB ligands can ameliorate PTH, because augmentation of eCB signaling has been demonstrated to mitigate migraine-like pathology and TBI induced neuronal damage. However, it is unknown how the eCB system can modulate the ascending and descending pain pathways in which eCB receptors and enzymes are substantially expressed. Based on previous findings including TBI, migraine, and other inflammatory and neuropathic pain models, we hypothesize that eCBs can modulate PTH in various regions (Figure 2). As mentioned above, the neuronal activity of TG neurons are regulated by CB1 receptor and eCBs. In addition to TG, mast cells activation such as degranulation is alleviated by a CB receptor agonist [129]. In the dural blood vessel, AEA caused vasodilation [147], in line with a fact that eCB degrading enzymes modulate the endothelium dependent vascular tone [148]. CGRP production is regulated in a CB1 receptor dependent manner in cervical spinal cord [126]. The increment of CGRP and substance P in orofacial pain model was reversed by the FAAH inhibitor in thalamus, hypothalamus, and mesencephalon [149], and microinjection of CB receptor agonist or antagonist modulated nociceptive response in brainstem, amygdala, and some nuclei in thalamus [150,151]. Among the pain regulating neural circuits, amygdala-mPFC pathway was well-addressed [152,153], since it is known that mPFC neuronal activity is attenuated by strong inhibitory signal from amygdala in the neuropathic pain model [154]. Basolateral amygdala pyramidal neurons project to GABAergic interneurons in mPFC, which predominantly express CB1 receptor. Under the pain state, GABAergic disinhibition was decreased since CB1 receptor expression was downregulated [153]. Therefore, mPFC pyramidal neuron activity was weakened, which leads to attenuation of the descending pain modulation. In addition, Neugebauer’s group reported that 2-AG tone in the mPFC pyramidal neurons was also lowered due to reduced mGluR5 mediated activation of 2-AG biosynthetic enzyme, DAGLα. Conversely, administration of agonists for mGluR5 and CB1 receptor restored GABAergic disinhibition and mPFC pyramidal neuron activity [152,155], which can further modulate the neuronal activity in PAG leading to descending inhibitory control of nociception [153]. Additionally, in the insular cortex, microinjection of the FAAH inhibitor attenuated hyperalgesia as well as neuronal activity in the region [156]. RVM and PAG are reciprocally connected modulating descending pain pathway in which the eCB signaling mediated by CB1 as well as CB2 receptor is deeply involved [157,158,159,160]. Microinjection of the CB agonists in PAG caused antinociceptive behavior [161] as well as reducing neuronal activity in RVM [162]. Conversely PAG neurons can modulate activity of RVM ON and OFF cells by injection of cannabidiol or FAAH inhibitor [162,163]. In fact, microinjection of CB1 agonist in the vlPAG attenuated the activity of trigeminal Aδ-fiber neurons that are activated by electric stimulation at the dura mater, suggesting that dural nociceptive response can be modulated from vlPAG through CB1 receptors [164].

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