GABA acting on GABAB receptors located in a medullary pain facilitatory area enhances nociceptive behaviors evoked by intraplantar formalin injection.
The dorsal reticular nucleus (DRt) plays a key role in facilitation of nociceptive transmission at the spinal cord. In this study, we evaluated the mechanisms involved in GABA-mediated control of the DRt focusing on the role of local GABAB receptors. First, we used in vivo microdialysis to study the release of GABA in the DRt during the course of the formalin test. An increase of GABA levels in comparison with baseline values was detected in the second phase of the test. Because we previously showed that GABAB receptors are expressed by opioidergic DRt neurons, which respond to nociceptive stimuli and inhibit spinally projecting DRt neurons involved in descending pronociception, we then interfered with local GABAB receptors using gene transfer and pharmacological approaches. Lentiviral-mediated knockdown of GABAB1a expression decreased nociceptive responses during the second phase of the test. Local administration of the GABAB receptor antagonist CGP 35348 also decreased nociceptive responses in the second phase of the test, whereas the opposite was detected after injection of the GABAB agonist baclofen. Finally, we determined the GABAergic afferents of the DRt, namely those arising from its main brain afferents, which are located at the telencephalon and diencephalon. For that purpose, we combined retrograde tract-tracing from the DRt with immunodetection of glutamate decarboxylase, the GABA-synthesizing enzyme. The higher numbers of retrogradely labelled glutamate decarboxylase-immunoreactive neurons were located at insular, somatosensory, and motor cortices. Collectively, the results suggest that GABA acting on GABAB receptors may enhance pain facilitation from the DRt during inflammatory pain.
Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Porto, Portugal IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Department of Biomonitoring and Sensoring, University of Groningen, Groningen, the Netherlands Brains On-Line BV, Groningen, the Netherlands Center for Health Technology and Services Research (CINTESIS), Porto, Portugal Screening and Test Evaluation Program, School of Public Health, The University of Sydney, Sydney, Australia Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Isabel
I
Martins
Paulina
P
Carvalho
Martin G
MG
de Vries
Armando
A
Teixeira-Pinto
Steven P
SP
Wilson
Ben H C
BHC
Westerink
Isaura
I
Tavares
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000633:toxicity; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D009619:Nociceptors / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism*; D012154:Reticular Formation / Q000166:cytology / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D005557:Formaldehyde; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; D001418:Baclofen