Mispositioned Neurokinin-1 Receptor-Expressing Neurons Underlie Heat Hyperalgesia in Disabled-1 Mutant Mice.

Abstract

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.

• Authors: Xidao Wang, Griselda M Yvone, Marianne Cilluffo, Ashley S Kim, Allan I Basbaum, Patricia E Phelps
• Journal: eNeuro (eNeuro) 2019 May/Jun Vol. 6 Issue 3 ISSN: 2373-2822 [Electronic] United States
• PMID: 31122949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Wang et al.

Chemical References

• Cell Adhesion Molecules, Neuronal
• Dab1 protein, mouse
• Extracellular Matrix Proteins
• Nerve Tissue Proteins
• Receptors, Neurokinin-1
• Reelin Protein
• Reln protein, mouse
• Serine Endopeptidases

Topics

• Animals
• Cell Adhesion Molecules, Neuronal (genetics, physiology)
• Extracellular Matrix Proteins (genetics, physiology)
• Hot Temperature
• Hyperalgesia (physiopathology)
• Male
• Mice, Knockout
• Nerve Tissue Proteins (genetics, physiology)
• Posterior Horn Cells (metabolism, physiology)
• Receptors, Neurokinin-1 (metabolism, physiology)
• Reelin Protein
• Serine Endopeptidases (genetics, physiology)
• Signal Transduction
• Spinal Cord (physiopathology)