Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics

Figure 2

Schematic strategy to achieve cell type specific application of optogenetics and DREADDs for the treatment of neuropathic pain. (a) To realize optogenetic- or DREADD-mediated stabilization of aberrant nociceptor activity in neuropathic pain, two viral vector systems can be employed. Relatively neuron selective serotypes of recombinant adeno-associated virus (rAAV) or herpes simplex virus (HSV) can be used to deliver viral constructs to dorsal root ganglion. To achieve conditional expression of channel rhodopsin or DREADDs, Cre recombinase or reverse tetracycline activated transcriptional activator (rtTA) is expressed under the control of promoters which are selectively activated in neuropathic pain affected nociceptors. (b) In case of the Cre-loxP system, viral expression of halorhodopsin (yellow light-gated chloride ion channel, eNpHR3.0) is prevented by loxP flanked transcription stop cassette (STOP) downstream of the strong promoter chicken beta actin (CBA). Transgene expression is only turned on in cells where Cre recombinase is expressed and STOP cassette is removed. (c) In Tet-On system, transgene expression is under the control of tetracycline responsive promoter (Tet promoter). Transgenes begin to be expressed in rtTA expressing nociceptors only when doxycycline is administered. Transgene expression can be controlled reversibly by withdrawing doxycycline. Following region specific expression of halorhodopsin or DREADDs in nociceptor, membrane stabilization can be induced by halorhodopsin activation by 580 nm light stimulation or CNO binding to inhibitory hM4Di-DREADDs.