The tongue is uniquely exposed to water-soluble environmental chemicals that may lead to injury or tumorigenesis. However, comparatively little research has focused on the molecular and functional organization of trigeminal ganglia (TG) afferent neurons innervating the tongue. The current study identified and characterized lingual sensory neurons based on a neuronal subtype classification previously characterized in the dorsal root ganglion (DRG) neurons. We employed immunohistochemistry on transgenic reporter mouse lines as well as single-cell PCR of known markers of neuronal subtypes to characterize neuronal subtypes innervating the tongue. Markers expressed in retrogradely labeled TG neurons were evaluated for the proportion of neurons expressing each marker, intensity of expression, and overlapping genes. We found that tongue-innervating sensory neurons primarily expressed CGRP, TRPV1, TrkC, 5HT3A and Parvalbumin. These markers correspond to peptidergic and a subgroup of non-peptidergic C-nociceptors, peptidergic A nociceptors, proprioceptors and myelinated low-threshold mechanoreceptors (LTMRs). Interestingly, as reported previously, we also found several differences between TG and DRG neurons indicating the need for single-cell sequencing of neuronal types based on tissue type within all TG as well as DRG neurons.

Supplemental Digital Content is Available in the Text.The study demonstrates a novel peripheral role of brain-derived neurotrophic factor or TrkB signaling in oral cancer pain. We show that brain-derived neurotrophic factor is expressed in human oral cancer cell and tumors and modulates tongue innervating sensory neurons by peripheral TrkB activities.

Chronic pain is the leading cause of disability worldwide 1 and commonly associated with comorbid disorders 2 . However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidize into pronociceptive oxylipins 3 , 4 . Here we report that mice administered a ω-6 PUFA-enriched diet develop persistent nociceptive hypersensitivities, spontaneously-active and hyper-responsive glabrous afferent fibers, and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated PLA2 activity. Pharmacological and molecular inhibition of PLA2g7 or diet reversal with high ω-3 PUFAs attenuate nociceptive behaviors, neurophysiologic abnormalities, and afferent histopathology induced by high ω-6 intake. Additionally, ω-6 PUFA accumulation exacerbates allodynia observed in preclinical inflammatory and neuropathic pain models, and is strongly correlated with multiple pain indices of clinical diabetic neuropathy. Collectively, these data reveal dietary enrichment with ω-6 PUFAs as a novel etiology of peripheral neuropathy and risk factor for chronic pain, and implicate multiple therapeutic considerations for clinical pain management.

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Chronic pain is the leading cause of disability worldwide 1 and commonly associated with comorbid disorders 2 . However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidize into pronociceptive oxylipins 3,4 . Here we report that mice administered a diet enriched with ω-6 PUFAs develop persistent nociceptive hypersensitivities, spontaneously-active and hyper-responsive glabrous afferent fibers, and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated PLA2 activity. Pharmacological and molecular inhibition of PLA2g7 or diet reversal with high ω-3 PUFAs attenuate nociceptive behaviors, neurophysiologic abnormalities, and afferent histopathology induced by high ω-6 intake. In addition, ω-6 accumulation exacerbates the intensity or duration of allodynia observed in preclinical inflammatory and neuropathic pain models, as well as in clinical diabetic neuropathy. Collectively, these data reveal diet as a novel etiology of peripheral neuropathy and risk factor for chronic pain, and implicate multiple therapeutic considerations for clinical pain management.