title: Multimodal distribution of human cold pain thresholds.
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.
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Violeta
authors.initials: V
authors.lastname: Dimova
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lieb
authors.affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Oertel
authors.affiliation: DataBionics Research Group, University of Marburg, Hans-Meerwein-Straße, 35032, Marburg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ultsch
mesh_terms: D000293:Adolescent; D000328:Adult; D015220:Calcium Channels / Q000378:metabolism; D003080:Cold Temperature; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology*; D012867:Skin / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000378:metabolism; D013697:Thermosensing / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D050051:Transient Receptor Potential Channels