Multimodal distribution of human cold pain thresholds

PLoS One. 2015 May 20;10(5):e0125822. doi: 10.1371/journal.pone.0125822. eCollection 2015.

Abstract

Background: It 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.

Methods: Cold 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.

Results: CPTs 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.

Conclusions: The 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Calcium Channels / metabolism
  • Cold Temperature
  • Female
  • Humans
  • Male
  • Nerve Tissue Proteins / metabolism
  • Pain Threshold / physiology*
  • Skin / metabolism
  • TRPA1 Cation Channel
  • TRPM Cation Channels / metabolism
  • Thermosensing / physiology*
  • Transient Receptor Potential Channels / metabolism
  • Young Adult

Substances

  • Calcium Channels
  • Nerve Tissue Proteins
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPM Cation Channels
  • TRPM8 protein, human
  • Transient Receptor Potential Channels

Grant support

This work was supported by the “Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz“: “LOEWE-Schwerpunkt: Anwendungsorientierte Arzneimittelforschung” (to JL) and the Research Training Group Translational Research Innovation – Pharma (TRIP) (to JL). The research has also received funding from the European Union Seventh Framework Programme (FP7/2007 - 2013) under grant agreement no 602919 (to JL). The funders had no role in method design, data selection and analysis, decision to publish, or preparation of the manuscript.