Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats

Abstract

Fast conducting myelinated high threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an AAV8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype specific with only AHTMR neurons being inhibited. One week following nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve injured animals were also increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states.

A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia

“…It appears that this protocol can be safely used to inhibit PBel CGRP neurons repeatedly with an interval of 5 min between inhibition trials, because there was no histological damage to the brain after laser exposure and because the animals had normal CO2 arousal during Laser-OFF trials performed after Laser-ON trials. ArchT has been used to silence neurons in vivo in a wide variety of recent studies (Boada et al, 2014;Campos et al, 2016;Daou et al, 2016;Kim et al, 2015;Shi et al, 2015;Stefanik et al, 2013;Stefanik and Kalivas, 2013;Tsunematsu et al, 2013), and this use has also been validated by extracellular recordings from neocortical areas (Chow et al, 2010;Chuong et al, 2014). It has recently been reported that ArchT activation may excite some terminals (Mahn et al, 2016) instead of inhibiting them, but that is unlikely to be the case in these experiments, as the results of using ArchT to inhibit the PBel CGRP terminals in the forebrain were very similar to those for using ArchT to inhibit the CGRP cell bodies in the PBel, and both were similar to the results of deleting Vglut2 from PBel CGRP neurons, or ablating them genetically (Kaur et al, 2013).…”

Nerve injury induced activation of fast-conducting high threshold mechanoreceptors predicts non-reflexive pain related behavior

“…Animals underwent right L5 pSNL and recovery as previously described [25]. In a sham control group, the surgical procedure was identical to that described except that the left L5 spinal nerve was not injured.…”

“…A geometric surface based on single cell fast-conducting, high-threshold mechanoreceptor (AHTMR) threshold to mechanical force after nerve or tissue injury was used to activate peripheral neuronal input [24,25]. We hypothesized that increasing calibrated force, related to reducing the size of the surface activated by a given pressure, would activate AHTMR differently due to nerve injury induced hypersensitivity.…”

Spotlight on pain: optogenetic approaches for interrogating somatosensory circuits

“…Optical manipulations of pain behaviors have also been achieved in nontransgenic animals using AAV vectors to transduce peripheral fibers [68]. More relevant clinically, viral delivery of the inhibitory opsins halorodopsin [68] or archaerhodopsin [19,85] to peripheral sensory neurons enabled light-dependent blunting of behavioral responses to thermal and mechanical stimulation [68,85]. Optical inhibition also reversed mechanical and thermal hypersensitivity in models of neuropathic pain [19,68], suggesting a possible therapeutic option for using optogenetics in treating chronic pain.…”