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.

Keywords: Cold; Cold allodynia; Dorsal root ganglion; Ion channels; Neuropathic pain; Nociception; Pain; Thermosensation.

Fig. 1

Schematic of human cold pain sensitivity in health and disease. In chronic pain conditions, the sensitivity to decreasing temperature is increased, which typically manifests as an increase in cold-induced pain. The dashed line represents the approximate threshold at which cooling begins to evoke noticeable pain in healthy individuals.

Fig. 2

Average estimated prevalence of cold-evoked pain in different human pain states. Data points represent the prevalence of pain evoked by cooling or cold stimuli reported among chronic pain patients in individual clinical studies (Baron et al., 2009, Bécouarn et al., 1998, Bengtsson et al., 1986, Bowsher, 2005, Cersosimo, 2005, Craigen et al., 1999, de Gramont et al., 2000, Díaz-Rubio et al., 1998, Dougherty et al., 2004, Forsyth et al., 1997, Halawa et al., 2010, Irwin et al., 1997, Kim and Choi-Kwon, 1999, Koroschetz et al., 2011, Lange et al., 1992, Laugier et al., 1979, Lawrence et al., 1980, Lithell et al., 1998, Machover et al., 1996, Nijhuis et al., 2010, Nurmikko et al., 1990, Ruijs et al., 2007, Toth et al., 2009, Vestergaard et al., 1995).

Fig. 3

In vivo calcium imaging of dorsal root ganglia reveals variable thermal activation thresholds of cold-sensing neurons (Luiz et al., 2019). (A) Normalised fluorescence response from 134 cold-sensitive neurons expressing GCaMP3 following a staircased (A.i.) or drop temperature stimulus (A.ii.). The cooling protocols are shown at the top of the figure. Each row represents the response from the same neuron to each stimulus protocol. (B) Summary of the threshold of cold-sensing neuron activation observed following a staircased cooling protocol as in (A.i.). (C) Number of neurons activated by different cooling temperature drops as in (A.ii.) (linear regression: y =  − 4.715 ∗ x + 142.4). (D) Histogram of cell area for cold-sensing neurons (Least squares Gaussian; Bin width is 60 μm²; Mean = 253.6 μm², Std. Dev. 76.06 μm²). (E) Relationship between mean thresholds of activation in response to a drop (DR) cooling stimulus versus a staircased (SC) cooling stimulus (linear regression: y = 0.8652 ∗ x + 0.3839). Error bars denote S.E.M.

Fig. 4

Ion channels defining low- and high-threshold cold-sensing neurons. Schematic illustrating the ion channels expressed in cold-sensing neurons that transduce cooling and control terminal excitability at low temperatures.