44 research outputs found
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Mispositioned Neurokinin-1 Receptor-Expressing Neurons Underlie Heat Hyperalgesia in Disabled-1 Mutant Mice.
Reelin (Reln) and Disabled-1 (Dab1) participate in the Reln-signaling pathway and when either is deleted, mutant mice have the same spinally mediated behavioral abnormalities, increased sensitivity to noxious heat and a profound loss in mechanical sensitivity. Both Reln and Dab1 are highly expressed in dorsal horn areas that receive and convey nociceptive information, Laminae I-II, lateral Lamina V, and the lateral spinal nucleus (LSN). Lamina I contains both projection neurons and interneurons that express Neurokinin-1 receptors (NK1Rs) and they transmit information about noxious heat both within the dorsal horn and to the brain. Here, we ask whether the increased heat nociception in Reln and dab1 mutants is due to incorrectly positioned dorsal horn neurons that express NK1Rs. We found more NK1R-expressing neurons in Reln-/- and dab1-/- Laminae I-II than in their respective wild-type mice, and some NK1R neurons co-expressed Dab1 and the transcription factor Lmx1b, confirming their excitatory phenotype. Importantly, heat stimulation in dab1-/- mice induced Fos in incorrectly positioned NK1R neurons in Laminae I-II. Next, we asked whether these ectopically placed and noxious-heat responsive NK1R neurons participated in pain behavior. Ablation of the superficial NK1Rs with an intrathecal injection of a substance P analog conjugated to the toxin saporin (SSP-SAP) eliminated the thermal hypersensitivity of dab1-/- mice, without altering their mechanical insensitivity. These results suggest that ectopically positioned NK1R-expressing neurons underlie the heat hyperalgesia of Reelin-signaling pathway mutants, but do not contribute to their profound mechanical insensitivity
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Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control.
The original formulation of Gate Control Theory (GCT) proposed that the perception of pain produced by spinal cord signaling to the brain depends on a balance of activity generated in large (nonnociceptive)- and small (nociceptive)-diameter primary afferent fibers. The theory proposed that activation of the large-diameter afferent "closes" the gate by engaging a superficial dorsal horn interneuron that inhibits the firing of projection neurons. Activation of the nociceptors "opens" the gate through concomitant excitation of projection neurons and inhibition of the inhibitory interneurons. Sixty years after publication of the GCT, we are faced with an ever-growing list of morphologically and neurochemically distinct spinal cord interneurons. The present Review highlights the complexity of superficial dorsal horn circuitry and addresses the question whether the premises outlined in GCT still have relevance today. By examining the dorsal horn circuits that underlie the transmission of "pain" and "itch" messages, we also address the extent to which labeled lines can be incorporated into a contemporary view of GCT
Transmitting Pain and Itch Messages: A Contemporary View of the Spinal Cord Circuits that Generate Gate Control
The original formulation of Gate Control Theory (GCT) proposed that the perception of pain produced by spinal cord signaling to the brain depends on a balance of activity generated in large (nonnociceptive)- and small (nociceptive)-diameter primary afferent fibers. The theory proposed that activation of the large-diameter afferent "closes" the gate by engaging a superficial dorsal horn interneuron that inhibits the firing of projection neurons. Activation of the nociceptors "opens" the gate through concomitant excitation of projection neurons and inhibition of the inhibitory interneurons. Sixty years after publication of the GCT, we are faced with an ever-growing list of morphologically and neurochemically distinct spinal cord interneurons. The present Review highlights the complexity of superficial dorsal horn circuitry and addresses the question whether the premises outlined in GCT still have relevance today. By examining the dorsal horn circuits that underlie the transmission of "pain" and "itch" messages, we also address the extent to which labeled lines can be incorporated into a contemporary view of GCT