αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors

Significance Pain is a societal burden with enormous economic and social costs. More than 50% of pain patients find current therapies unsatisfactory. A major reason for this pharmacological failure is our limited understanding of the cellular processes underlying pain. Algesic sensitization of nociceptors is a complex event in pain transduction that involves the potentiation of thermosensory channels. The molecular mechanisms remain controversial because of nociceptor heterogeneity that suggests the existence of cell-type–specific strategies. We show that algesic sensitization of transient receptor potential vanilloid 1 (TRPV1) involves the exocytotic recruitment of new receptors in peptidergic nociceptors and the modulation of channel gating in nonpeptidergic sensory neurons. Furthermore, algesic delivery of TRPV1 channels is concomitant with pro-inflammatory neuropeptide secretion, ensuring rapid modulation of pain transduction. Proalgesic sensitization of peripheral nociceptors in painful syndromes is a complex molecular process poorly understood that involves mobilization of thermosensory receptors to the neuronal surface. However, whether recruitment of vesicular thermoTRP channels is a general mechanism underlying sensitization of all nociceptor types or is subtype-specific remains controversial. We report that sensitization-induced Ca2+-dependent exocytotic insertion of transient receptor potential vanilloid 1 (TRPV1) receptors to the neuronal plasma membrane is a mechanism specifically used by peptidergic nociceptors to potentiate their excitability. Notably, we found that TRPV1 is present in large dense-core vesicles (LDCVs) that were mobilized to the neuronal surface in response to a sensitizing insult. Deletion or silencing of calcitonin-gene–related peptide alpha (αCGRP) gene expression drastically reduced proalgesic TRPV1 potentiation in peptidergic nociceptors by abrogating its Ca2+-dependent exocytotic recruitment. These findings uncover a context-dependent molecular mechanism of TRPV1 algesic sensitization and a previously unrecognized role of αCGRP in LDCV mobilization in peptidergic nociceptors. Furthermore, these results imply that concurrent secretion of neuropeptides and channels in peptidergic C-type nociceptors facilitates a rapid modulation of pain signaling.