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GABA(A) receptor facilitation of neurokinin release from primary afferent terminals in the rat spinal cord.
Neuroscience. 2005; 130(4):1013-27.N

Abstract

Our goal was to test the following hypotheses: 1) GABA(A) receptors facilitate neurokinin release from primary afferent terminals; 2) they do this by suppressing an inhibitory effect of GABA(B) receptors; 3) the activation of these two receptors is controlled by the firing frequency of primary afferents. We evoked neurokinin release by stimulating the dorsal root attached to spinal cord slices, and measured it using neurokinin 1 receptor (NK1R) internalization. Internalization evoked by root stimulation at 1 Hz (but not at 100 Hz) was increased by the GABA(A) receptor agonists muscimol (effective concentration of drug for 50% of the increase [EC50] 3 microM) and isoguvacine (EC50 4.5 microM). Internalization evoked by root stimulation at 100 Hz was inhibited by the GABA(A) receptor antagonists bicuculline (effective concentration of drug for 50% of the inhibition [IC50] 2 microM) and picrotoxin (IC50 243 nM). Internalization evoked by incubating the root with capsaicin (to selectively recruit nociceptive fibers) was increased by isoguvacine and abolished by picrotoxin. Therefore, GABA(A) receptors facilitate neurokinin release. Isoguvacine-facilitated neurokinin release was inhibited by picrotoxin, low Cl-, low Ca2+, Ca2+ channel blockers and N-methyl-D-aspartate receptor antagonists. Bumetanide, an inhibitor of the Na(+)-K(+)-2Cl- cotransporter, inhibited isoguvacine-facilitated neurokinin release, but this could be attributed to a direct inhibition of GABA(A) receptors. The GABA(B) agonist baclofen inhibited NK1R internalization evoked by 100 Hz root stimulation (IC50 1.5 microM), whereas the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP-55845) increased NK1R internalization evoked by 1 Hz root stimulation (EC50 21 nM). Importantly, baclofen inhibited isoguvacine-facilitated neurokinin release, and CGP-55845 reversed the inhibition of neurokinin release by bicuculline. In conclusion, 1) GABA(B) receptors located presynaptically in primary afferent terminals inhibit neurokinin release; 2) GABA(A) receptors located in GABAergic interneurons facilitate neurokinin release by suppressing GABA release onto these GABA(B) receptors; 3) high frequency firing of C-fibers stimulates neurokinin release by activating GABA(A) receptors and inhibiting GABA(B) receptors, whereas low frequency firing inhibits neurokinin release by the converse mechanisms.

Authors+Show Affiliations

Center for Neurovisceral Sciences and Women's Health, CURE: Digestive Diseases Research Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15652997

Citation

Lao, L, and J C G. Marvizón. "GABA(A) Receptor Facilitation of Neurokinin Release From Primary Afferent Terminals in the Rat Spinal Cord." Neuroscience, vol. 130, no. 4, 2005, pp. 1013-27.
Lao L, Marvizón JC. GABA(A) receptor facilitation of neurokinin release from primary afferent terminals in the rat spinal cord. Neuroscience. 2005;130(4):1013-27.
Lao, L., & Marvizón, J. C. (2005). GABA(A) receptor facilitation of neurokinin release from primary afferent terminals in the rat spinal cord. Neuroscience, 130(4), 1013-27.
Lao L, Marvizón JC. GABA(A) Receptor Facilitation of Neurokinin Release From Primary Afferent Terminals in the Rat Spinal Cord. Neuroscience. 2005;130(4):1013-27. PubMed PMID: 15652997.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GABA(A) receptor facilitation of neurokinin release from primary afferent terminals in the rat spinal cord. AU - Lao,L, AU - Marvizón,J C G, PY - 2004/10/10/accepted PY - 2005/1/18/pubmed PY - 2005/5/12/medline PY - 2005/1/18/entrez SP - 1013 EP - 27 JF - Neuroscience JO - Neuroscience VL - 130 IS - 4 N2 - Our goal was to test the following hypotheses: 1) GABA(A) receptors facilitate neurokinin release from primary afferent terminals; 2) they do this by suppressing an inhibitory effect of GABA(B) receptors; 3) the activation of these two receptors is controlled by the firing frequency of primary afferents. We evoked neurokinin release by stimulating the dorsal root attached to spinal cord slices, and measured it using neurokinin 1 receptor (NK1R) internalization. Internalization evoked by root stimulation at 1 Hz (but not at 100 Hz) was increased by the GABA(A) receptor agonists muscimol (effective concentration of drug for 50% of the increase [EC50] 3 microM) and isoguvacine (EC50 4.5 microM). Internalization evoked by root stimulation at 100 Hz was inhibited by the GABA(A) receptor antagonists bicuculline (effective concentration of drug for 50% of the inhibition [IC50] 2 microM) and picrotoxin (IC50 243 nM). Internalization evoked by incubating the root with capsaicin (to selectively recruit nociceptive fibers) was increased by isoguvacine and abolished by picrotoxin. Therefore, GABA(A) receptors facilitate neurokinin release. Isoguvacine-facilitated neurokinin release was inhibited by picrotoxin, low Cl-, low Ca2+, Ca2+ channel blockers and N-methyl-D-aspartate receptor antagonists. Bumetanide, an inhibitor of the Na(+)-K(+)-2Cl- cotransporter, inhibited isoguvacine-facilitated neurokinin release, but this could be attributed to a direct inhibition of GABA(A) receptors. The GABA(B) agonist baclofen inhibited NK1R internalization evoked by 100 Hz root stimulation (IC50 1.5 microM), whereas the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP-55845) increased NK1R internalization evoked by 1 Hz root stimulation (EC50 21 nM). Importantly, baclofen inhibited isoguvacine-facilitated neurokinin release, and CGP-55845 reversed the inhibition of neurokinin release by bicuculline. In conclusion, 1) GABA(B) receptors located presynaptically in primary afferent terminals inhibit neurokinin release; 2) GABA(A) receptors located in GABAergic interneurons facilitate neurokinin release by suppressing GABA release onto these GABA(B) receptors; 3) high frequency firing of C-fibers stimulates neurokinin release by activating GABA(A) receptors and inhibiting GABA(B) receptors, whereas low frequency firing inhibits neurokinin release by the converse mechanisms. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/15652997/GABA_A__receptor_facilitation_of_neurokinin_release_from_primary_afferent_terminals_in_the_rat_spinal_cord_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(04)00960-1 DB - PRIME DP - Unbound Medicine ER -