Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor

S D Ugarte; G E Homanics; L L Firestone; D L Hammond

doi:10.1016/s0306-4522(99)00481-9

Back

Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor

Journal article

Peer reviewed

Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor

S D Ugarte, G E Homanics, L L Firestone and D L Hammond

Neuroscience, Vol.95(3), pp.795-806

2000

DOI: 10.1016/s0306-4522(99)00481-9

PMID: 10670447

View Online

Abstract

A line of mice was recently created in which the gabrb3 gene, which encodes the beta3 subunit of the GABA(A) receptor, was inactivated by gene-targeting. The existence of mice with a significantly reduced population of GABA(A) receptors in the CNS enabled an investigation of the role of GABA and GABA(A) receptors in nociception. The present study examined the sensory thresholds of these mice, as well as the antinociceptive effects of subcutaneously or intrathecally administered GABA(A) and GABA(B) receptor agonists. Homozygous null (beta3-/-) mice displayed enhanced responsiveness to low-intensity thermal stimuli in the tail-flick and hot-plate test compared to C57BL/6J and 129/SvJ progenitor strain mice, and their wild-type (beta3+/+) and heterozygous (beta3+/-) littermates. The beta3-/- mice also exhibited enhanced responsiveness to innocuous tactile stimuli compared to C57BL/6J, 129/SvJ and to their beta3+/+ littermates as assessed by von Frey filaments. The presence of thermal hyperalgesia and tactile allodynia in beta3-/- mice is consistent with a loss of inhibition mediated by presynaptic and postsynaptic GABA(A) receptors in the spinal cord. As expected, subcutaneous administration of the GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol did not produce antinociception in beta3-/- mice, whereas it produced a dose-dependent increase in hot-plate latency in C57BL/6J, 129/SvJ, beta3+/+ and beta3+/- mice. However, the antinociceptive effect of the GABA(B) receptor agonist baclofen in the tail-flick and hot-plate tests was also reduced in beta3-/- mice compared to the progenitor strains, beta3+/+ or beta3+/- mice after either subcutaneous or intrathecal administration. This finding was unexpected and suggests that a reduction in GABA(A) receptors can affect the production of antinociception by other analgesic drugs as well.

Baclofen - pharmacology

Injections, Spinal

Physical Stimulation

Mice, Inbred Strains - genetics

Baclofen - administration & dosage

GABA Agonists - administration & dosage

Hot Temperature

Sex Characteristics

Receptors, GABA-A - deficiency

Isoxazoles - administration & dosage

Isonicotinic Acids - pharmacology

Isoxazoles - pharmacology

Animals

Isonicotinic Acids - administration & dosage

Sensory Thresholds - physiology

Injections, Subcutaneous

Receptors, GABA-A - genetics

GABA Agonists - pharmacology

Mice, Inbred C57BL - genetics

Mice

Protein Isoforms - deficiency

Nociceptors - drug effects

Protein Isoforms - genetics

Details

Title: Subtitle: Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the beta3 subunit of the GABA(A) receptor
Creators: S D Ugarte - Department of Anesthesia and Critical Care, University of Chicago, Illinois, USA
G E Homanics
L L Firestone
D L Hammond
Resource Type: Journal article
Publication Details: Neuroscience, Vol.95(3), pp.795-806
Publisher: United States
DOI: 10.1016/s0306-4522(99)00481-9
PMID: 10670447
ISSN: 0306-4522
eISSN: 1873-7544
Grant note: T32GM07151 / NIGMS NIH HHS DE11423 / NIDCR NIH HHS AA10422 / NIAAA NIH HHS
Language: English
Date published: 2000
Academic Unit: Iowa Neuroscience Institute; Nursing; Anesthesia; Neuroscience and Pharmacology
Record Identifier: 9984006425802771

Metrics

18 Record Views

60 Times Cited - Web of Science

See more details