TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity

Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway. [Display omitted] •Neuronal activity enhances sensory modality of nociceptors•This effect is due to USP5/T-type channel-mediated dorsal horn plasticity•This sensitization process is not self-propagating•This process may underlie a protective pain state Stemkowski et al. establish that sensory modality of nociceptors can be enhanced by neuronal activity in the absence of physical injury. This process is dependent on a T-type calcium channel-mediated enhancement of dorsal horn synaptic activity that derives from activity-induced upregulation of USP5 expression.