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Spinal antinociceptive effect of gastrin releasing peptide (GRP) via GABAergic inhibitory interneurons expressing the GRP receptor (GRPR)

Akiyama T, Tominaga M, Davoodi A, Nagamine M, Takamori K, Carstens MI, Carstens E (2014) Spinal antinociceptive effect of gastrin releasing peptide (GRP) via GABAergic inhibitory interneurons expressing the GRP receptor (GRPR). Neuroscience 2014 Abstracts 158.02. Society for Neuroscience, Washington, DC.

Summary: GRPR-expressing dorsal horn neurons signal itch. We investigated a role for such neurons in modulating the spinal neurotransmission of mechanical and heat pain in mice. In behavioral studies, we measured heat and mechanical paw withdrawal thresholds using Hargreaves and von Frey assays, respectively. Mice received intrathecal (it) administration of one of following (5 µL volume); bombesin (6.2 pmol), GRP (0.1 nmol), and GRPR antagonists RC-3095 (0.03 nmol) and BW2258U89 (1.5 nmol). It administration of bombesin or GRP significantly reduced both heat and mechanical withdrawal thresholds with a maximal effect 10 min post-administration. In contrast, it administration of RC-3095 and BW2258U89 significantly increased both heat and mechanical withdrawal thresholds with a maximal effect 10 min post-administration. Mice treated with it bombesin-saporin to ablate GRPR-expressing spinal neurons exhibited reduced heat and mechanical withdrawal thresholds. It GRP failed to elicit heat and mechanical hyperalgesia in these mice. In electrophysiological recordings from superficial lumbar dorsal horn neurons, either bombesin or RC-3095 was spinally applied during responses elicited by noxious mechanical or heat stimulation of the cutaneous receptive field on the hindpaw. Bombesin increased both noxious mechanical- and heat-evoked activity in bombesin-sensitive neurons, while RC-3095 decreased noxious heat-evoked activity. In bombesin-insensitive neurons, bombesin decreased both noxious mechanical- and heat-evoked activity, while RC-3095 increased both. We additionally employed a double-label strategy to investigate if GRPR-expressing dorsal horn neurons coexpressed GABA, a molecular marker of inhibitory interneurons. Approximately 10% of GRPR-positive neurons were immunopositive for GABA. These results indicate that a subset of GRPR-expressing neurons function as interneurons in a circuit that suppresses nociceptive transmission in the dorsal horn. Noxious mechanical and heat stimuli activate GRPR-expressing dorsal horn neurons. A GABAergic subset of these may serve as inhibitory interneurons that contribute to inhibition of spinal neurons signaling heat and mechanical pain. Alternatively, GRPR-expressing neurons may drive other subsets of inhibitory interneurons. The antinociceptive circuit described here can be activated by pruritogens. We propose that the relative activity in antinociceptive and antipruritic circuits within the dorsal horn modulates itch- and pain-signaling ascending neurons to result in the perception of itch or pain.

Related Products: Bombesin-SAP (Cat. #IT-40)