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Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception.
J Physiol 2019; 597(13):3425-3439JP

Abstract

KEY POINTS

While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.

ABSTRACT

It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.

Authors+Show Affiliations

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31077379

Citation

Loeza-Alcocer, Emanuel, et al. "Peripheral GABA Receptors Regulate Colonic Afferent Excitability and Visceral Nociception." The Journal of Physiology, vol. 597, no. 13, 2019, pp. 3425-3439.
Loeza-Alcocer E, McPherson TP, Gold MS. Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception. J Physiol (Lond). 2019;597(13):3425-3439.
Loeza-Alcocer, E., McPherson, T. P., & Gold, M. S. (2019). Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception. The Journal of Physiology, 597(13), pp. 3425-3439. doi:10.1113/JP278025.
Loeza-Alcocer E, McPherson TP, Gold MS. Peripheral GABA Receptors Regulate Colonic Afferent Excitability and Visceral Nociception. J Physiol (Lond). 2019;597(13):3425-3439. PubMed PMID: 31077379.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception. AU - Loeza-Alcocer,Emanuel, AU - McPherson,Thomas P, AU - Gold,Michael S, Y1 - 2019/06/02/ PY - 2019/03/18/received PY - 2019/05/10/accepted PY - 2020/07/01/pmc-release PY - 2019/5/12/pubmed PY - 2019/5/12/medline PY - 2019/5/12/entrez KW - extrinsic innervation KW - sensitization KW - sensory neuron KW - sensory transduction SP - 3425 EP - 3439 JF - The Journal of physiology JO - J. Physiol. (Lond.) VL - 597 IS - 13 N2 - KEY POINTS: While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain. ABSTRACT: It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/31077379/Peripheral_GABA_receptors_regulate_colonic_afferent_excitability_and_visceral_nociception L2 - https://doi.org/10.1113/JP278025 DB - PRIME DP - Unbound Medicine ER -