The trigeminal nerve (V) is the fifth and largest of all cranial nerves, and it is responsible for detecting sensory stimuli that arise from the craniofacial area. The nerve is divided into three branches: ophthalmic (V1), maxillary (V2), and mandibular (V3); their cell bodies are located in the trigeminal ganglia and they make connections with second-order neurons in the trigeminal brainstem sensory nuclear complex. Ascending projections via the trigeminothalamic tract transmit information to the thalamus and other brain regions responsible for interpreting sensory information. One of the most common forms of craniofacial pain is trigeminal neuralgia. Trigeminal neuralgia is characterized by sudden, brief, and excruciating facial pain attacks in one or more of the V branches, leading to a severe reduction in the quality of life of affected patients. Trigeminal neuralgia etiology can be classified into idiopathic, classic, and secondary. Classic trigeminal neuralgia is associated with neurovascular compression in the trigeminal root entry zone, which can lead to demyelination and a dysregulation of voltage-gated sodium channel expression in the membrane. These alterations may be responsible for pain attacks in trigeminal neuralgia patients. The antiepileptic drugs carbamazepine and oxcarbazepine are the first-line pharmacological treatment for trigeminal neuralgia. Their mechanism of action is a modulation of voltage-gated sodium channels, leading to a decrease in neuronal activity. Although carbamazepine and oxcarbazepine are the first-line treatment, other drugs may be useful for pain control in trigeminal neuralgia. Among them, the anticonvulsants gabapentin, pregabalin, lamotrigine and phenytoin, baclofen, and botulinum toxin type A can be coadministered with carbamazepine or oxcarbazepine for a synergistic approach. New pharmacological alternatives are being explored such as the active metabolite of oxcarbazepine, eslicarbazepine, and the new Nav1.7 blocker vixotrigine. The pharmacological profiles of these drugs are addressed in this review.

Highlights d Dopamine projections from the VTA innervate the mPFC d Dopamine release in the mPFC reverses mechanical hypersensitivity in SNI mice d Dopamine release induces conditioned place preference in SNI mice d Dopamine inputs increase activity of mPFC neurons projecting to the vlPAG

Cav3.2 calcium channels are important mediators of nociceptive signaling in the primary afferent pain pathway, and their expression is increased in various rodent models of chronic pain. Previous work from our laboratory has shown that this is in part mediated by an aberrant expression of deubiquitinase USP5, which associates with these channels and increases their stability. Here, we report on a novel bioactive rhodanine compound (II-1), which was identified in compound library screens. II-1 inhibits biochemical interactions between USP5 and the Cav3.2 domain III-IV linker in a dose-dependent manner, without affecting the enzymatic activity of USP5. Molecular docking analysis reveals two potential binding pockets at the USP5-Cav3.2 interface that are distinct from the binding site of the deubiquitinase inhibitor WP1130 (a.k.a. degrasyn). With an understanding of the ability of some rhodanines to produce false positives in high-throughput screening, we have conducted several orthogonal assays to confirm the validity of this hit, including in vivo experiments. Intrathecal delivery of II-1 inhibited both phases of formalin-induced nocifensive behaviors in mice, as well as abolished thermal hyperalgesia induced by the delivery of complete Freund’s adjuvant (CFA) to the hind paw. The latter effects were abolished in Cav3.2 null mice, thus confirming that Cav3.2 is required for the action of II-1. II-1 also mediated a robust inhibition of mechanical allodynia induced by injury to the sciatic nerve. Altogether, our data uncover a novel class of analgesicswell suited to rapid structure–activity relationship studiesthat target the Cav3.2/USP5 interface.