GABA acting on GABA_B receptors located in a medullary pain facilitatory area enhances nociceptive behaviors evoked by intraplantar formalin injection

Abstract

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 GABA_B 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 GABA_B 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 GABA_B receptors using gene transfer and pharmacological approaches. Lentiviral-mediated knockdown of GABA_B1a expression decreased nociceptive responses during the second phase of the test. Local administration of the GABA_B receptor antagonist CGP 35348 also decreased nociceptive responses in the second phase of the test, whereas the opposite was detected after injection of the GABA_B 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 GABA_B receptors may enhance pain facilitation from the DRt during inflammatory pain.

In Brief

GABA is released in the dorsal reticular in response to formalin injection in the hind paw.