While some therapies are available for the treatment of trigeminal neuralgia and related conditions, a review of the literature shows the efficacy of long-term pain management in most patients is limited at best. Several key receptors and ion channels involved in nociception are localized in trigeminal primary afferent neurons, many of which display unique patterns of expression and distribution compared to sensory afferents located elsewhere in the peripheral nervous system. P2X3, an ionotropic ATP receptor implicated in nociceptive mechanisms, is more abundant on trigeminal primary afferents than analogous extracranial neurons, suggesting a likely target for novel treatment of trigeminal neuralgia and related deep-tissue craniofacial pain conditions. In addition, P2X3 is often coexpressed with ASIC3 in neuron terminals as well as the neuropeptides CGRP and SP in the trigeminal ganglion. Thus, this review focuses on the role of P2X3 and the coexpressed ASIC3 and neuropeptides in neuropathic nociception, as well as their potential as therapeutic targets. Neuropeptide antagonists such as those already successfully used in the treatment of migraine are currently the most promising candidates for use in pain management for trigeminal neuralgia patients. The efficacy of future therapies might be maximized if multiple sites of the putative nociceptive functional complexes in craniofacial nerves are targeted, including P2X3, ASIC3, CGRP, and SP.
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