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.
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- Steven A Prescott
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experimental procedures were approved by the Animal Care Committee at the Hospital for Sick Children (Animal Use Protocol #22919 and #22576) and were performed in accordance to guidelines from the Canadian Council on Animal Care. For in vivo experiments, animals were anesthetized with urethane (20% in normal saline; 1.2 g/kg i.p.). To prepare slices for in vitro experiments, animals were anesthetized with 4% isoflurane.
- Claire Wyart, Hôpital Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, France
© 2019, Lee et al.
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