TRPV1 activity and substance P release are required for corneal cold nociception

AbstractAs a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8+ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8+ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8+ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8+ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.

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cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord

Neuropharmacology ◽

10.1016/j.neuropharm.2021.108533 ◽

2021 ◽

pp. 108533

Author(s):

Wenling Chen ◽

James A. McRoberts ◽

Helena S. Ennes ◽

Juan Carlos Marvizon

Keyword(s):

Spinal Cord ◽

Protein Kinase ◽

Substance P ◽

Protein Kinase A ◽

Camp Signaling ◽

Rat Spinal Cord ◽

P Release ◽

Substance P Release ◽

Kinase A

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Calcium and capsaicin- induced substance P release from peripheral terminals of primary sensory neurons

Regulatory Peptides ◽

10.1016/0167-0115(88)90337-0 ◽

1988 ◽

Vol 22 (1-2) ◽

pp. 117 ◽

Cited By ~ 14

Author(s):

C.A. Maggi ◽

P. Santicioli ◽

P. Geppetti ◽

R. Patacchini ◽

E. Del Bianco ◽

...

Keyword(s):

Substance P ◽

Sensory Neurons ◽

Primary Sensory Neurons ◽

P Release ◽

Substance P Release

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Sufentanil, Morphine, Met-enkephalin, and k-Agonist (U-50,488H) Inhibit Substance P Release from Primary Sensory Neurons

Anesthesiology ◽

10.1097/00000542-198904000-00022 ◽

1989 ◽

Vol 70 (4) ◽

pp. 672-677 ◽

Cited By ~ 48

Author(s):

H. Ming Chang ◽

Charles B. Berde ◽

George G. Holz ◽

Grieg F. Steward ◽

Richard M. Kream

Keyword(s):

Substance P ◽

Sensory Neurons ◽

Primary Sensory Neurons ◽

P Release ◽

Inhibit Substance ◽

Substance P Release

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Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Journal of Clinical Investigation ◽

10.1172/jci117928 ◽

1995 ◽

Vol 95 (5) ◽

pp. 2359-2366 ◽

Cited By ~ 38

Author(s):

A Garland ◽

J E Jordan ◽

J Necheles ◽

L E Alger ◽

M M Scully ◽

...

Keyword(s):

Substance P ◽

Primary Culture ◽

P Release ◽

C Fiber ◽

Substance P Release

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Effects of General Anesthetics on Substance P Release and c-Fos Expression in the Spinal Dorsal Horn

Anesthesiology ◽

10.1097/aln.0b013e31829996b6 ◽

2013 ◽

Vol 119 (2) ◽

pp. 433-442 ◽

Cited By ~ 5

Author(s):

Toshifumi Takasusuki ◽

Shigeki Yamaguchi ◽

Shinsuke Hamaguchi ◽

Tony L. Yaksh

Keyword(s):

Nitrous Oxide ◽

Substance P ◽

Dorsal Horn ◽

Receptor Internalization ◽

General Anesthetics ◽

Neurokinin 1 Receptor ◽

P Release ◽

Fos Expression ◽

Neurokinin 1 ◽

Substance P Release

Abstract Background: The authors examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn. Methods: Rats received saline, propofol (100 mg/kg), pentobarbital (50 mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%), or fentanyl (30 μg/kg). During anesthesia, rats received intraplantar 5% formalin (50 μl) to left hind paw. Ten minutes later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of neurokinin 1 receptor internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 h and c-Fos expression measured. Results: Intraplantar formalin-induced robust neurokinin 1 receptor internalization in ipsilateral dorsal horn (ipsilateral: 54 ± 6% [mean ± SEM], contralateral: 12 ± 2%; P < 0.05; n = 4). Fentanyl, but not propofol, pentobarbital, isoflurane, nor nitrous oxide alone inhibited neurokinin 1 receptor internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced neurokinin 1 receptor internalization (27 ± 3%; P < 0.05; n = 5). All agents reduced c-Fos expression (control: 34 ± 4, fentanyl: 8 ± 2, isoflurane: 12 ± 3, nitrous oxide: 11 ± 2, isoflurane + nitrous oxide: 12 ± 1, pentobarbital: 11 ± 2, propofol: 13 ± 3; P < 0.05; n = 3). Conclusion: General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism that is independent of an effect on small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggest a correlative rationale for the therapeutic use of these anesthetic protocols by blocking nociceptive afferent transmitter release and preventing the initiation of cascade, which is immediately postsynaptic to the primary afferent.

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