Abstract
Inflammatory pain is thought to arise from increased transmission from nociceptors and recruitment of 'silent' afferents. To evaluate inflammation-induced changes, mice expressing GCaMP3 in cutaneous sensory neurons were generated and neuronal responses to mechanical stimulation in vivo before and after subcutaneous infusion of an 'inflammatory soup' (IS) were imaged in an unanesthetized preparation. Infusion of IS rapidly altered mechanical responsiveness in the majority of neurons. Surprisingly, more cells lost, rather than gained, sensitivity and 'silent' afferents that were mechanically insensitive and gained mechanosensitivity after IS exposure were rare. However, the number of formerly 'silent' afferents that became mechanosensitive was increased five fold when the skin was heated briefly prior to infusion of IS. These findings suggest that pain arising from inflamed skin reflects a dramatic shift in the balance of sensory input, where gains and losses in neuronal populations results in novel output that is ultimately interpreted by the CNS as pain.
Highlights
Increased pain from stimulation of inflamed tissues is generally thought to arise from nociceptors that have become more responsive to mechanical stimuli as a result of exposure to inflammatory mediators released at the site of injury
Previous studies based on single cell electrophysiological approaches have been limited in their ability to assess the development of sensitization within a population of neurons due to spatial and
GCaMP3 immunofluorescence and calcium signaling in dorsal root ganglion (DRG) neurons in vitro
Summary
Increased pain from stimulation of inflamed tissues is generally thought to arise from nociceptors that have become more responsive to mechanical stimuli as a result of exposure to inflammatory mediators released at the site of injury. Inflammation may recruit ’silent’ afferents that are normally unresponsive to mechanical stimuli but gain mechanical sensitivity de novo in the presence of chemical mediators, providing novel input to pain pathways (Davis et al, 1993; Feng and Gebhart, 2011; Habler et al, 1990; Meyer et al, 1991; Neugebauer et al, 1989; Schmelz et al, 1994; Schmidt et al, 1995; Xu et al, 2000). Previous studies based on single cell electrophysiological approaches have been limited in their ability to assess the development of sensitization within a population of neurons due to spatial and
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