Optogenetic Inhibition of CGRPα Sensory Neurons Reveals Their Distinct Roles in Neuropathic and Incisional Pain

Abstract

Cutaneous somatosensory neurons convey innocuous and noxious mechanical, thermal, and chemical stimuli from peripheral tissues to the CNS. Among these are nociceptive neurons that express calcitonin gene-related peptide-α (CGRPα). The role of peripheral CGRPα neurons (CANs) in acute and injury-induced pain has been studied using diphtheria toxin ablation, but their functional roles remain controversial. Because ablation permanently deletes a neuronal population, compensatory changes may ensue that mask the physiological or pathophysiological roles of CANs, particularly for injuries that occur after ablation. Therefore, we sought to define the role of intact CANs under baseline and injury conditions by using noninvasive transient optogenetic inhibition. We assessed pain behavior longitudinally from acute to chronic time points. We generated adult male and female mice that selectively express the outward rectifying proton pump archaerhodopsin-3 (Arch) in CANs, and inhibited their peripheral cutaneous terminals in models of neuropathic (spared nerve injury) and inflammatory (skin-muscle incision) pain using transdermal light activation of Arch. After nerve injury, brief activation of Arch reversed the chronic mechanical, cold, and heat hypersensitivity, alleviated the spontaneous pain, and reversed the sensitized mechanical currents in primary afferent somata. In contrast, Arch inhibition of CANs did not alter incision-induced hypersensitivity. Instead, incision-induced mechanical and heat hypersensitivity was alleviated by peripheral blockade of CGRPα peptide-receptor signaling. These results reveal that CANs have distinct roles in the time course of pain during neuropathic and incisional injuries and suggest that targeting peripheral CANs or CGRPα peptide-receptor signaling could selectively treat neuropathic or postoperative pain, respectively. The contribution of sensory afferent CGRPα neurons (CANs) to neuropathic and inflammatory pain is controversial. Here, we left CANs intact during neuropathic and perioperative incision injury by using transient transdermal optogenetic inhibition of CANs. We found that peripheral CANs are required for neuropathic mechanical, cold, and heat hypersensitivity, spontaneous pain, and sensitization of mechanical currents in afferent somata. However, they are dispensable for incisional pain transmission. In contrast, peripheral pharmacological inhibition of CGRPα peptide-receptor signaling alleviated the incisional mechanical and heat hypersensitivity, but had no effect on neuropathic pain. These results show that CANs have distinct roles in neuropathic and incisional pain and suggest that their targeting via novel peripheral treatments may selectively alleviate neuropathic versus incisional pain.

Optogenetic Stimulation of The Motor Cortex Alleviates Neuropathic Pain in Rats of Infraorbital Nerve Injury With/Without CGRP Knock-Down

“…Additional studies have reported that treatment with a CGRP antagonist decreases injury-induced mechanical hypersensitivity. (13,14,(28)(29)(30)(31). The ndings of the present study are in accordance with previous observations of improvements as animal with α-CGRP inhibition following optic stimulation showed better improvement in hypersensitivity than animals treated with optical stimulation alone.…”

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

“…In addition, other researchers generated adult mice selectively expressing the outward rectifying proton pump archaerhodopsin in peripheral neurons expressing calcitonin gene-related peptide-α (CANs), and inhibited their peripheral cutaneous terminals in models of SNI with a transdermal light system activation. After SNI surgery, the authors found that brief activation of archeo-rhodopsin on their peripheral cutaneous terminals reversed chronic mechanical, cold, and heat hypersensitivity [136]. In addition, the role of optogenetic stimulations of glia cells has been as well investigated.…”

Silent cold-sensing neurons drive cold allodynia in neuropathic pain states

“…10 Tellingly, optogenetic inhibition of CGRPα-positive neurons transiently and reversibly relieves cold allodynia after spared nerve injury. 58 Ciguatoxins also increase CGRP release and produce flare when injected into humans. 59,60 Using in vivo imaging of the trigeminal ganglion, CGRPα-positive neurons were identified as a mixture of small-diameter polymodal nociceptors that respond to heat and large-diameter mechanonociceptors that respond to noxious mechanical stimulation of the hairy skin.…”