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Molecular mechanisms of cold pain.

ABSTRACT: The sensation of cooling is essential for survival. Extreme cold is a noxious stimulus that drives protective behaviour and that we thus perceive as pain. However, chronic pain patients suffering from cold allodynia paradoxically experience innocuous cooling as excruciating pain. Peripheral sensory neurons that detect decreasing temperature express numerous cold-sensitive and voltage-gated ion channels that govern their response to cooling in health and disease. In this review, we discuss how these ion channels control the sense of cooling and cold pain under physiological conditions, before focusing on the molecular mechanisms by which ion channels can trigger pathological cold pain. With the ever-rising number of patients burdened by chronic pain, we end by highlighting the pressing need to define the cells and molecules involved in cold allodynia and so identify new, rational drug targets for the analgesic treatment of cold pain.

SUBMITTER: MacDonald DI

PROVIDER: S-EPMC7025288 | biostudies-literature | 2020 Jan-Jul

REPOSITORIES: biostudies-literature

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Molecular mechanisms of cold pain.

MacDonald Donald Iain DI Wood John N JN Emery Edward C EC

Neurobiology of pain (Cambridge, Mass.) 20200128

The sensation of cooling is essential for survival. Extreme cold is a noxious stimulus that drives protective behaviour and that we thus perceive as pain. However, chronic pain patients suffering from cold allodynia paradoxically experience innocuous cooling as excruciating pain. Peripheral sensory neurons that detect decreasing temperature express numerous cold-sensitive and voltage-gated ion channels that govern their response to cooling in health and disease. In this review, we discuss how th ...[more]

PMID: 32090187

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Project description:BackgroundIt is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.MethodsCold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit.ResultsCPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively.ConclusionsThe localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.

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Molecular mechanisms of cold pain.

Publications

Molecular mechanisms of cold pain.

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