Effect of Fatty Acid Amide Hydrolase Inhibitor URB597 on Orofacial Pain Perception in Rats

Abstract

Endocannabinoids act as analgesic agents in a number of headache models. However, their effectiveness varies with the route of administration and the type of pain. In this study, we assessed the role of the fatty acid amide hydrolase inhibitor URB597 in an animal model of orofacial pain based on tooth pulp stimulation. More specifically, we assessed the effects of intracerbroventricular (i.c.v.) and intraperitoneal (i.p.) administration of URB597 on the amplitude of evoked tongue jerks (ETJ) in rats. The levels of the investigated mediators anandamide (AEA), 2-arachidonyl glycerol (2-AG), Substance P (SP), calcitonin-gene-related peptide (CGRP), endomorphin-2 (EM-2) and fatty acid amide hydrolase (FAAH) inhibitor by URB597 and receptors cannabinoid type-1 receptors (CB1R), cannabinoid type-2 receptors (CB2R) and µ-opioid receptors (MOR) were determined in the mesencephalon, thalamus and hypothalamus tissues. We have shown that increasing endocannabinoid AEA levels by both central and peripheral inhibition of FAAH inhibitor by URB597 has an antinociceptive effect on the trigemino-hypoglossal reflex mediated by CB1R and influences the activation of the brain areas studied. On the other hand, URB597 had no effect on the concentration of 2-AG in the examined brain structures and caused a significant decrease in CB2R mRNA expression in the hypothalamus only. Tooth pulp stimulation caused in a significant increase in SP, CGRP and EM-2 gene expression in the midbrain, thalamus and hypothalamus. In contrast, URB597 administered peripherally one hour before stimulation decreased the mRNA level of these endogenous neuropeptides in comparison with the control and stimulation in all examined brain structures. Our results show that centrally and peripherally administered URB597 is effective at preventing orofacial pain by inhibiting AEA catabolism and reducing the level of CGRP, SP and EM-2 gene expression and that AEA and 2-AG have different species and model-specific regulatory mechanisms. The data presented in this study may represent a new promising therapeutic target in the treatment of orofacial pain.

Effect of MCH1, a fatty-acid amide hydrolase inhibitor, on the depressive-like behavior and gene expression of endocannabinoid and dopaminergic-signaling system in the mouse nucleus accumbens

“…In vitro evidence suggests that CB1 activation can increase Cnr1 mRNA expression via extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling ( 36 ). Our results are are in agreement with previous studies showing an increase of Cnr1 mRNA expression after 1.5 h of URB597 administration in a pain perception model in rats, although this was evidenced in the mesencephalon, thalamus, and hypothalamus but not in the striatum ( 37 ). Another study also revealed an increase in Cnr1 mRNA expression in the hippocampus after 2 weeks of URB597 treatment in a chronic constriction injury pain model in rats ( 38 ).…”

The surgical anatomy of the inferior alveolar nerve: a meta-analysis with clinical implications

“…Furthermore, the section of the nerve in front of the mental foramen and just before its ramification to the incisive nerve has been defined as the anterior loop of the IAN. The IAN transmits pain signals from mandibular teeth, gingiva of the mandible, and the lower lip [43].…”

Role of neuropeptides in orofacial pain: A literature review

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Orofacial pain, with a prevalence of 10%-26%, constitutes a severe medical and social problem. 1 It results from impaired branch of the trigeminal nerve or the spread of neurogenic inflammation to the orofacial region, 1 which is not independent but rather the primary symptom of a group of disorders that occur in the orofacial region with pain. Orofacial pain encompasses dental pain, temporomandibular joint (TMJ) pain, orofacial migraine, trigeminal neuralgia, myofascial pain and mucositis pain.

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“…perceptual, emotional and cognitive) through several routes, such as that involving primary afferent fibres (Aδ and C-fibre), trigeminal ganglion (TG), trigeminal nucleus caudalis (SpVc), and ventral posterior medial nucleus (VPM) and several areas of the cerebral cortex. 1,4,5 In this classic nociceptive pathway, TG or SpVc neurons transcellularly communicate with peripheral glia cells and immune inflammatory cells through various mediators (inflammatory cytokines, neuropeptides and ion channels), receptor mechanisms, and signalling processes, leading to TG or SpVc neuronal hyperexcitability followed by orofacial pain hypersensitivity. 6,7 Among the aforementioned mediators, neuropeptides have been widely studied in the last four decades.…”