Abstract
Neuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia - the misperception of light touch as painful - occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.
Highlights
Neuropathic pain results from damage to or dysfunction of the nervous system
Compared with the punctate allodynia evoked by stimuli like von Frey hairs, dynamic allodynia is more troubling for patients (Hansson, 2003)
Dorsal horn neuron receptive fields (RFs) have been reported to change on a short timescale, consistent with an RF shaped by the balance of excitatory and inhibitory input rather than being “hard wired” (Cook et al, 1987; Dubuisson et al, 1979; Laird and Cervero, 1989; McMahon and Wall, 1984)
Summary
Neuropathic pain results from damage to or dysfunction of the nervous system. It affects ~10% of the population (van Hecke et al, 2014) and is notoriously difficult to treat (Woolf, 2010). Hypersensitivity to tactile stimulation is a troubling feature of such pain This so-called mechanical allodynia can be acutely reproduced by blocking synaptic inhibition at the spinal level (Miraucourt et al, 2009; Sivilotti and Woolf, 1994; Sorkin and Puig, 1996; Sorkin et al, 1998; Yaksh, 1989). Disinhibition can result from reduced activation of GABAA or glycine receptors, or from reduced current flow through activated receptors. The former has several possible causes (Zeilhofer et al, 2012) but the latter stems uniquely from dysregulation of intracellular chloride due to KCC2 hypofunction (Coull et al, 2003). Enhancing KCC2 function reverses injury-induced allodynia (Gagnon et al, 2013; Lavertu et al, 2014; Mapplebeck et al, in press), demonstrating that chloride dysregulation contributes significantly to injury-induced disinhibition
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