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

Overview

Journal eNeuro

Specialty Neurology

Date 2019 May 25

PMID 31122949

Citations 1

Authors

Xidao Wang

Griselda M Yvone

Marianne Cilluffo

Ashley S Kim

Allan I Basbaum

Patricia E Phelps

Affiliations

Soon will be listed here.

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 and mutants is due to incorrectly positioned dorsal horn neurons that express NK1Rs. We found more NK1R-expressing neurons in and 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 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 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.

Citing Articles

Reelin dorsal horn neurons co-express Lmx1b and are mispositioned in disabled-1 mutant mice.

Yvone G, Chavez-Martinez C, Nguyen A, Wang D, Phelps P Eur J Neurosci. 2020; 52(5):3322-3338.

PMID: 32492253 PMC: 9451954. DOI: 10.1111/ejn.14847.

References

Liu H, Brown J, Jasmin L, Maggio J, Vigna S, Mantyh P . Synaptic relationship between substance P and the substance P receptor: light and electron microscopic characterization of the mismatch between neuropeptides and their receptors. Proc Natl Acad Sci U S A. 1994; 91(3):1009-13. PMC: 521443. DOI: 10.1073/pnas.91.3.1009. View

Todd A . Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010; 11(12):823-36. PMC: 3277941. DOI: 10.1038/nrn2947. View

Yvone G, Zhao-Fleming H, Udeochu J, Chavez-Martinez C, Wang A, Hirose-Ikeda M . Disabled-1 dorsal horn spinal cord neurons co-express Lmx1b and function in nociceptive circuits. Eur J Neurosci. 2017; 45(5):733-747. PMC: 5486991. DOI: 10.1111/ejn.13520. View

Caviness Jr V, Frost D . Thalamocortical projections in the reeler mutant mouse. J Comp Neurol. 1983; 219(2):182-202. DOI: 10.1002/cne.902190205. View

Terashima T, Inoue K, Inoue Y, Mikoshiba K . Thalamic connectivity of the primary motor cortex of normal and reeler mutant mice. J Comp Neurol. 1987; 257(3):405-21. DOI: 10.1002/cne.902570309. View

Muller T, Brohmann H, Pierani A, Heppenstall P, Lewin G, Jessell T . The homeodomain factor lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron. 2002; 34(4):551-62. DOI: 10.1016/s0896-6273(02)00689-x. View

Olave M, Maxwell D . Axon terminals possessing alpha2C-adrenergic receptors densely innervate neurons in the rat lateral spinal nucleus which respond to noxious stimulation. Neuroscience. 2004; 126(2):391-403. DOI: 10.1016/j.neuroscience.2004.03.049. View

Peirs C, Seal R . Neural circuits for pain: Recent advances and current views. Science. 2016; 354(6312):578-584. PMC: 11327866. DOI: 10.1126/science.aaf8933. View

Phelps P, Rich R, Rios Y, Wong T . Evidence for a cell-specific action of Reelin in the spinal cord. Dev Biol. 2002; 244(1):180-98. DOI: 10.1006/dbio.2002.0580. View

10.

Peirs C, Williams S, Zhao X, Walsh C, Gedeon J, Cagle N . Dorsal Horn Circuits for Persistent Mechanical Pain. Neuron. 2015; 87(4):797-812. PMC: 4562334. DOI: 10.1016/j.neuron.2015.07.029. View

11.

Howell B, Gertler F, Cooper J . Mouse disabled (mDab1): a Src binding protein implicated in neuronal development. EMBO J. 1997; 16(1):121-32. PMC: 1169619. DOI: 10.1093/emboj/16.1.121. View

12.

Wang X, Zhang J, Eberhart D, Urban R, Meda K, Solorzano C . Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron. 2013; 78(2):312-24. PMC: 3700415. DOI: 10.1016/j.neuron.2013.03.001. View

13.

Terashima T, Inoue K, Inoue Y, Mikoshiba K, Tsukada Y . Distribution and morphology of callosal commissural neurons within the motor cortex of normal and reeler mice. J Comp Neurol. 1985; 232(1):83-98. DOI: 10.1002/cne.902320108. View

14.

DArcangelo G, Miao G, Curran T . Detection of the reelin breakpoint in reeler mice. Brain Res Mol Brain Res. 1996; 39(1-2):234-6. DOI: 10.1016/0169-328x(96)00046-0. View

15.

Suzuki R, Morcuende S, Webber M, Hunt S, Dickenson A . Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci. 2002; 5(12):1319-26. DOI: 10.1038/nn966. View

16.

Akopians A, Babayan A, Beffert U, Herz J, Basbaum A, Phelps P . Contribution of the Reelin signaling pathways to nociceptive processing. Eur J Neurosci. 2008; 27(3):523-37. DOI: 10.1111/j.1460-9568.2008.06056.x. View

17.

Cheng L, Arata A, Mizuguchi R, Qian Y, Karunaratne A, Gray P . Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat Neurosci. 2004; 7(5):510-7. DOI: 10.1038/nn1221. View

18.

Todd A, Spike R, Young S, Puskar Z . Fos induction in lamina I projection neurons in response to noxious thermal stimuli. Neuroscience. 2005; 131(1):209-17. DOI: 10.1016/j.neuroscience.2004.11.001. View

19.

Cheng L, Duan B, Huang T, Zhang Y, Chen Y, Britz O . Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat Neurosci. 2017; 20(6):804-814. PMC: 5470641. DOI: 10.1038/nn.4549. View

20.

Rahman W, Suzuki R, Hunt S, Dickenson A . Selective ablation of dorsal horn NK1 expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones. Neuropharmacology. 2008; 54(8):1208-14. DOI: 10.1016/j.neuropharm.2008.03.014. View