Abstract
Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Nav1.8 and CGRPα. Ablating neurons expressing Nav1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of Kv1 voltage-gated potassium channels. Thus, silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.
Highlights
Chronic pain patients suffering from cold allodynia experience normally innocuous cooling as excruciating pain (Jensen and Finnerup, 2014)
Silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability
To investigate the mechanisms of cold allodynia, we used in vivo calcium imaging to explore how sensory neuron responses to cooling are altered during chemotherapy-induced neuropathy
Summary
Chronic pain patients suffering from cold allodynia experience normally innocuous cooling as excruciating pain (Jensen and Finnerup, 2014). Cold detection involves cooling-gated ion channels like Trpm, as well as sodium and potassium channels that control excitability at low temperatures (Bautista et al, 2007; Colburn et al, 2007; Dhaka et al, 2007; Zimmermann et al, 2007; Madrid et al, 2009; Morenilla-Palao et al, 2014; Lolignier et al, 2015; Luiz et al, 2019). Mouse knockout studies suggest cold allodynia requires TRP channels and potassium channels expressed by unmyelinated C fibres (Alloui et al, 2006; Colburn et al, 2007; Noël et al, 2009; Descoeur et al, 2011; Nassini et al, 2011; Vetter et al, 2012; Knowlton et al, 2013; Pereira et al, 2014; González et al, 2017). Mechanistic investigation of the cells and molecules driving cold allodynia has proved difficult because of the challenge in recording large numbers of cold-responsive afferents, as well as the limitations of cold pain behaviour tests (Mckemy, 2010)
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