Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain

Abstract

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of nociceptive sensory afferents could be used to modulate bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the sensory neuron-specific sodium channel (sns) gene to selectively silence these neurons. Optically silencing nociceptive sensory afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of nociceptive sensory afferents in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of nociceptive sensory afferents reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naïve mice. These results suggest that selective optogenetic silencing of nociceptive bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain.

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience

“…Use cases will also need to be organized based on expectations, separating near-term and long-term needs. New computational neuroscience users, use cases, and applications will arise in other specialties as they consider the innervation of other organs ( Barth et al, 2017 ; Samineni et al, 2017 ; Vaseghi et al, 2017 ; Ross et al, 2018 ).…”

“…Non-targeted electrostimulation using transcranial electrodes is also being widely used but remains controversial, and lacks precise clinical indications ( Lefaucheur et al, 2014 ; Esmaeilpour et al, 2017 ; Huang et al, 2017 ; Lafon et al, 2017 ; Santos et al, 2017 ). Consideration is also being given to future use of optogenetic stimulation therapies that would offer still greater precision compared to electrical stimulation – targeting not only a particular area but a particular cell type or set of cell types within that area ( Vierling-Claassen et al, 2010 ; Kerr et al, 2014 ; Samineni et al, 2017 ). All such stimulation protocols require identification of suitable, if not necessarily optimal, ranges of parameters, e.g., strength, duration, frequency, waveform, location, iterations, schedule, reference activity, etc.…”

Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation

“…Expression of ChR2 in the CNS has been used to study a number of behaviors, including those related to anxiety, learning, and depression (Huber et al, 2008 ; Covington et al, 2010 ; Tye et al, 2011 ). Recently, optogenetic modulation of bladder smooth muscle was shown to elicit voiding in vivo (Park et al, 2017 ), and our group demonstrated that inhibition of sensory afferent activity via archaerhodopsin, a light-activated proton pump, attenuates pain-related behavior in the context of bladder inflammation (Samineni et al, 2017a ). The present study is an important addition that demonstrates for the first time the effects of direct, selective neuronal activation of distinct bladder afferents on behavioral correlates of bladder sensation and function.…”

A wireless closed-loop system for optogenetic peripheral neuromodulation

“…DRGs were sectioned and stained as previously described 38 . Briefly, 6-8 days after HSV viral vector injection, rats were perfused with PBS and 4% PFA as described above.…”