Tags

Type your tag names separated by a space and hit enter

Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice.
Gastroenterology 2019; 157(2):522-536.e2G

Abstract

BACKGROUND & AIMS

Proper colon function requires signals from extrinsic primary afferent neurons (ExPANs) located in spinal ganglia. Most ExPANs express the vanilloid receptor TRPV1, and a dense plexus of TRPV1-positive fibers is found around myenteric neurons. Capsaicin, a TRPV1 agonist, can initiate activity in myenteric neurons and produce muscle contraction. ExPANs might therefore form motility-regulating synapses onto myenteric neurons. ExPANs mediate visceral pain, and myenteric neurons mediate colon motility, so we investigated communication between ExPANs and myenteric neurons and the circuits by which ExPANs modulate colon function.

METHODS

In live mice and colon tissues that express a transgene encoding the calcium indicator GCaMP, we visualized levels of activity in myenteric neurons during smooth muscle contractions induced by application of capsaicin, direct colon stimulation, stimulation of ExPANs, or stimulation of preganglionic parasympathetic neuron (PPN) axons. To localize central targets of ExPANs, we optogenetically activated TRPV1-expressing ExPANs in live mice and then quantified Fos immunoreactivity to identify activated spinal neurons.

RESULTS

Focal electrical stimulation of mouse colon produced phased-locked calcium signals in myenteric neurons and produced colon contractions. Stimulation of the L6 ventral root, which contains PPN axons, also produced myenteric activation and contractions that were comparable to those of direct colon stimulation. Surprisingly, capsaicin application to the isolated L6 dorsal root ganglia, which produced robust calcium signals in neurons throughout the ganglion, did not activate myenteric neurons. Electrical activation of the ganglia, which activated even more neurons than capsaicin, did not produce myenteric activation or contractions unless the spinal cord was intact, indicating that a complete afferent-to-efferent (PPN) circuit was necessary for ExPANs to regulate myenteric neurons. In TRPV1-channel rhodopsin-2 mice, light activation of ExPANs induced a pain-like visceromotor response and expression of Fos in spinal PPN neurons.

CONCLUSIONS

In mice, ExPANs regulate myenteric neuron activity and smooth muscle contraction via a parasympathetic spinal circuit, linking sensation and pain to motility.

Authors+Show Affiliations

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience at the University of Pittsburgh, Pittsburgh, Pennsylvania.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience at the University of Pittsburgh, Pittsburgh, Pennsylvania.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience at the University of Pittsburgh, Pittsburgh, Pennsylvania.University of Toledo, Department of Neurosciences, Toledo, Ohio.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience at the University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: kaa@pitt.edu.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience at the University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: bmd1@pitt.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31075226

Citation

Smith-Edwards, Kristen M., et al. "Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice." Gastroenterology, vol. 157, no. 2, 2019, pp. 522-536.e2.
Smith-Edwards KM, Najjar SA, Edwards BS, et al. Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice. Gastroenterology. 2019;157(2):522-536.e2.
Smith-Edwards, K. M., Najjar, S. A., Edwards, B. S., Howard, M. J., Albers, K. M., & Davis, B. M. (2019). Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice. Gastroenterology, 157(2), pp. 522-536.e2. doi:10.1053/j.gastro.2019.04.034.
Smith-Edwards KM, et al. Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice. Gastroenterology. 2019;157(2):522-536.e2. PubMed PMID: 31075226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice. AU - Smith-Edwards,Kristen M, AU - Najjar,Sarah A, AU - Edwards,Brian S, AU - Howard,Marthe J, AU - Albers,Kathryn M, AU - Davis,Brian M, Y1 - 2019/05/08/ PY - 2019/03/08/received PY - 2019/04/08/revised PY - 2019/04/22/accepted PY - 2019/5/11/pubmed PY - 2019/5/11/medline PY - 2019/5/11/entrez KW - Enteric Nervous System KW - GCaMP KW - Gastrointestinal KW - TRPV1 SP - 522 EP - 536.e2 JF - Gastroenterology JO - Gastroenterology VL - 157 IS - 2 N2 - BACKGROUND & AIMS: Proper colon function requires signals from extrinsic primary afferent neurons (ExPANs) located in spinal ganglia. Most ExPANs express the vanilloid receptor TRPV1, and a dense plexus of TRPV1-positive fibers is found around myenteric neurons. Capsaicin, a TRPV1 agonist, can initiate activity in myenteric neurons and produce muscle contraction. ExPANs might therefore form motility-regulating synapses onto myenteric neurons. ExPANs mediate visceral pain, and myenteric neurons mediate colon motility, so we investigated communication between ExPANs and myenteric neurons and the circuits by which ExPANs modulate colon function. METHODS: In live mice and colon tissues that express a transgene encoding the calcium indicator GCaMP, we visualized levels of activity in myenteric neurons during smooth muscle contractions induced by application of capsaicin, direct colon stimulation, stimulation of ExPANs, or stimulation of preganglionic parasympathetic neuron (PPN) axons. To localize central targets of ExPANs, we optogenetically activated TRPV1-expressing ExPANs in live mice and then quantified Fos immunoreactivity to identify activated spinal neurons. RESULTS: Focal electrical stimulation of mouse colon produced phased-locked calcium signals in myenteric neurons and produced colon contractions. Stimulation of the L6 ventral root, which contains PPN axons, also produced myenteric activation and contractions that were comparable to those of direct colon stimulation. Surprisingly, capsaicin application to the isolated L6 dorsal root ganglia, which produced robust calcium signals in neurons throughout the ganglion, did not activate myenteric neurons. Electrical activation of the ganglia, which activated even more neurons than capsaicin, did not produce myenteric activation or contractions unless the spinal cord was intact, indicating that a complete afferent-to-efferent (PPN) circuit was necessary for ExPANs to regulate myenteric neurons. In TRPV1-channel rhodopsin-2 mice, light activation of ExPANs induced a pain-like visceromotor response and expression of Fos in spinal PPN neurons. CONCLUSIONS: In mice, ExPANs regulate myenteric neuron activity and smooth muscle contraction via a parasympathetic spinal circuit, linking sensation and pain to motility. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/31075226/Extrinsic_Primary_Afferent_Neurons_Link_Visceral_Pain_to_Colon_Motility_Through_a_Spinal_Reflex_in_Mice L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(19)36727-7 DB - PRIME DP - Unbound Medicine ER -