Role of the Excitability Brake Potassium Current IKDin Cold Allodynia Induced by Chronic Peripheral Nerve Injury.
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 IKDHere we studied the role of IKDin 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. IKDdensity 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 IKDand TRPM8, showing that a reduction in IKDcurrent 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 IKDin both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration.SIGNIFICANCE STATEMENTThis paper unveils the critical role of the brake potassium current IKDin 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 IKDis 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 IKDin both high-threshold cold thermoreceptors and nociceptors expressing TRPM8, providing a general model for this form of cold-induced pain.
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile.
Alejandro
0000-0001-7513-2516
A
González
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile.
Gonzalo
G
Ugarte
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile.
Carlos
C
Restrepo
Centro Interdisciplinario de Neurociencia de Valparaíso and Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso, 2340000 Valparaíso, Chile, and.
Gaspar
0000-0002-9277-6652
G
Herrera
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile.
Ricardo
R
Piña
University College London, Cell and Biology Department, W1CE 6BT London, United Kingdom.
José Antonio
JA
Gómez-Sánchez
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile.
María
M
Pertusa
Centro Interdisciplinario de Neurociencia de Valparaíso and Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso, 2340000 Valparaíso, Chile, and.
Patricio
0000-0003-0332-8098
P
Orio
Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, 9160000 Santiago, Chile, rodolfo.madrid@usach.cl.
Rodolfo
0000-0002-8623-5761
R
Madrid
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003080:Cold Temperature / Q000009:adverse effects*; D003198:Computer Simulation; D006930:Hyperalgesia / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology*; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008959:Models, Neurological; D009619:Nociceptors / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology*; D011188:Potassium / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*
D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D011188:Potassium
4-AP; Kv1 channels; PBMC; TRPM8; thermotransduction; α-DTx