Abstract
BackgroundDisinhibition of neurons in the superficial spinal dorsal horn, via microglia – neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain.ResultsHere we show that peripheral nerve injury, local spinal administration of ATP-stimulated microglia or pharmacological disruption of chloride transport change the phenotype of spinal lamina I output neurons, causing them to 1) increase the gain of nociceptive responsiveness, 2) relay innocuous mechanical input and 3) generate spontaneous bursts of activity. The changes in the electrophysiological phenotype of lamina I neurons may account for three principal components of neuropathic pain: hyperalgesia, mechanical allodynia and spontaneous pain, respectively.ConclusionThe transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.
Highlights
Disinhibition of neurons in the superficial spinal dorsal horn, via microglia – neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain
Hyperalgesia involves enhanced pain perception to noxious stimuli; allodynia designates pain experienced in response to an innocuous stimulus and spontaneous pain refers to recurring pain, not necessarily related to an identifiable peripheral stimulus
We have discovered that following peripheral nerve injury such disinhibition of spinal dorsal horn neurons occurs by a collapse of the anion gradient in lamina I neurons [7] via a novel microglia-neuron
Summary
Disinhibition of neurons in the superficial spinal dorsal horn, via microglia – neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. Hyperalgesia involves enhanced pain perception to noxious stimuli; allodynia designates pain experienced in response to an innocuous stimulus and spontaneous pain refers to recurring pain, not necessarily related to an identifiable peripheral stimulus. Of these symptoms, tactile allodynia (e.g. pain induced by gentle mechanical stimulation of the skin) and spontaneous pain are the most prevalent and debilitating [2]. We have discovered that following peripheral nerve injury such disinhibition of spinal dorsal horn neurons occurs by a collapse of the anion gradient in lamina I neurons [7] via a novel microglia-neuron (page number not for citation purposes)
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