Role of the Excitability Brake Potassium Current I_KDin Cold Allodynia Induced by Chronic Peripheral Nerve Injury

Abstract

Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms underlying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly determined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current I Here we studied the role of I in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. I density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathematical model of CSNs, including I and TRPM8, showing that a reduction in I current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of I in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. This paper unveils the critical role of the brake potassium current I in damage-triggered cold allodynia. Using a well-known form of nerve injury and combining behavioral analysis, calcium imaging, patch clamping, and pharmacological tools, validated by mathematical modeling, we determined that the functional expression of I is reduced in sensory neurons in response to peripheral nerve damage. This downregulation not only enhances cold sensitivity of high-threshold cold thermoreceptors signaling cold discomfort, but it also transforms a subpopulation of polymodal nociceptors signaling pain into neurons activated by mild temperature drops. Our results suggest that cold allodynia is linked to a reduction of I in both high-threshold cold thermoreceptors and nociceptors expressing TRPM8, providing a general model for this form of cold-induced pain.

Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons

“…Thus, TASK-3 and HCN channels, though important for cold detection, are unlikely to mediate the differences in intrinsic excitability between these two populations. Future studies are needed to determine whether other potassium conductances, such as those mediated Kv1 Gonzalez et al, 2017a;Gonzalez et al, 2017b), contribute to differences in intrinsic excitability between menthol-sensitive andinsensitive DRG neurons.…”

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

“…In vitro experiments suggest that cold allodynia results from a shift in cellular activation thresholds such that neurons signalling extreme cold are now active at higher temperatures. 27 In contrast, oxaliplatin did not affect thermal activation thresholds of basal cold-sensing neurons in vivo, when the hindpaw was stimulated with a range of temperature drops delivered by a Peltiercontrolled thermode ( Figure 1E). 20 Moreover, when we quantified peak fluorescence intensity in response to cold as a surrogate for excitability before and after oxaliplatin, cold-evoked fluorescence intensity in both the basal and silent populations in the oxaliplatin group was no different to vehicle ( Figure 1F).…”

“…6 Conversely, cold-sensitive nociceptors that usually respond to extreme cold may become activated to milder temperature drops and consequently trigger cooling-evoked pain. 27,32 Finally, cold-insensitive nociceptors that provide noxious sensory input could acquire a de novo sensitivity to cooling. 10,23 Using in vivo imaging, we found that activation of normally silent, large-diameter coldsensing neurons is a common mechanism of cold allodynia in three clinically important, but etiologically-distinct, neuropathic pain states.…”

“…[13][14][15][16][17][18][19][20] Studies of ion channel knockout mice suggest cold allodynia is maintained by canonical TRP channels and potassium channels expressed by unmyelinated C fibres. 8,14,[21][22][23][24][25][26][27] A role for sodium channels enriched in A fibres is also evident, however. 23,[28][29][30] Mechanistic investigation of the cells and molecules driving cold allodynia has so far proved difficult because of the challenge in recording large numbers of cold-responsive afferents, as well as the limitations of traditional cold pain behaviour tests.…”

The sensory coding of warm perception

“…Another possibility is that functional TRPM8 channels are required to provide information about temperature changes to enable warm perception. We addressed the likelihood of these two scenarios by acutely inactivating TRPM8 in the forepaw of wild type mice, using PBMC (1-Phenylethyl(2-aminoethyl)(4-benzyloxy)-3methoxybenzyl)carbamate), a selective antagonist of TRPM8 that has been shown to suppress cooling-responsive cells and to reduce cooling-evoked behavioural responses in mice (González et al, 2017;Knowlton et al, 2011;Yudin et al, 2016). We first trained wild type animals to report warming stimuli and, once mice were able to successfully report warming, we pharmacologically inactivated TRPM8 by performing a transdermal injection in the plantar side of the right forepaw and tested their warming perception ability ( Figure 7A,B).…”