Excitatory Superficial Dorsal Horn Interneurons Are Functionally Heterogeneous and Required for the Full Behavioral Expression of Pain and Itch

Abstract

SUMMARY To what extent dorsal horn interneurons contribute to the modality specific processing of pain and itch messages is not known. Here we report that loxp/cre-mediated CNS deletion of TR4, a testicular orphan nuclear receptor, results in loss of many excitatory interneurons in the superficial dorsal horn, but preservation of primary afferents and spinal projection neurons. The interneuron loss is associated with a near complete absence of supraspinally-integrated pain and itch behaviors, elevated mechanical withdrawal thresholds and loss of nerve injury-induced mechanical hypersensitivity, but reflex responsiveness to noxious heat, nerve injury-induced heat hypersensitivity and tissue injury-induced heat and mechanical hypersensitivity are intact. We conclude that different subsets of dorsal horn excitatory interneurons contribute to tissue and nerve injury-induced heat and mechanical pain and that the full expression of supraspinally-mediated pain and itch behaviors cannot be generated solely by nociceptor and pruritoceptor activation of projection neurons; concurrent activation of excitatory interneurons is essential.

Itch Mechanisms and Circuits

“…It is comprehensible that the perception of sensation by the brain requires the engagement of projection neurons, as well as the excitatory and inhibitory interneurons that regulate the activity of projection neurons. Direct evidence about the role of excitatory interneurons in the behavioral responses evoked by pruritogens came from the analysis of TR4 conditional knockout mice (148). Neuronal deletion of TR4, a testicular orphan nuclear receptor, results in preservation of primary afferent neurons and spinal projection neurons, as well as the loss of many excitatory interneurons in the superficial dorsal horn.…”

“…Neuronal deletion of TR4, a testicular orphan nuclear receptor, results in preservation of primary afferent neurons and spinal projection neurons, as well as the loss of many excitatory interneurons in the superficial dorsal horn. Spinal projection neurons in TR4 conditional knockout mice exhibit decreased responsiveness to both noxious stimuli and pruritogens; these changes are associated with the attenuated pain and itch behavioral responses, demonstrating the importance of the concurrent activation of excitatory neurons for transmitting sensory information (148). …”

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

“…Transmission through those polysynaptic chains is under tight inhibitory control, as evidenced by the consequences of disinhibition (Section 8). Indeed, evidence points to excitatory interneurons being crucial for the development of neuropathic pain, 82,83 and it appears equally true that inhibitory control of those excitatory neurons is key. Inhibitory interneurons are also implicated in the control of itch.…”

Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch

“…Recent studies indicate that independent dorsal horn circuits transmit the pruritoceptive and nociceptive information that generates itch and pain (1)(2)(3)(4)(5)(6)(7)(8)(9). For example, although primary afferent nociceptors that express the capsaicin receptor TRPV1 convey both noxious and pruritic stimuli to the spinal cord dorsal horn, recent evidence indicates that different spinal circuits are engaged.…”