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The Gastrointestinal Hormone Ghrelin Modulates Inhibitory Neurotransmission in Deep Laminae of Mouse Spinal Cord Dorsal Horn

Department of Veterinary Morphophysiology (A.M.V., F.F., C.S., L.L., M.B., A.M.), University of Turin, 10095 Grugliasco (Torino) Italy; and Istituto Nazionale di Neuroscienze (L.L., A.M.), 10125 Torino, Italy

Address all correspondence and requests for reprints to: Adalberto Merighi, Department of Veterinary Morphophysiology, Via Leonardo da Vinci 44, 10095 Grugliasco (TO), Italy. E-mail: adalberto.merighi{at}unito.it.

Ghrelin is mainly described for its effects on feeding behavior and metabolism. However, central nervous system distribution of its receptor [type 1a GH secretagogue receptor (GHSR)] and modulation of neurotransmission in the hypothalamus suggest broader effects than originally predicted. Systemically administrated ghrelin inhibits inflammatory pain after behavioral observations. Therefore, we investigated the expression and function of type 1a GHSR in mouse spinal cord by molecular biology, biochemistry, histology, and electrophysiology. The mRNA and protein were detected in tissue extracts by RT-PCR and Western blotting. In situ, receptor mRNA and immunoreactivity were localized to cell bodies within the medial aspect of the deep dorsal horn. Patch clamp recordings on laminae IV–VI demonstrated that bath-applied ghrelin (100 nM) induced a strong increase of spontaneous -aminobutyric acid/glycine-mediated current frequency (463 ± 93% of the control) and amplitude (150 ± 16% of the control) in about 60% of recorded neurons. Specificity of type 1a GHSR activation was confirmed by the lack of effect of the deacylated form of ghrelin (des-acyl-ghrelin) and after preincubation with the specific receptor antagonist [D-Lys³]GHRP-6. In the presence of tetrodotoxin, the effect of the peptide was strongly reduced, mainly indicating an action potential-dependent mechanism. The functional link between ghrelin and pain was confirmed by inhibition in vitro of the c-fos response to capsaicin activation of nociceptive fibers, after quantification of Fos-immunoreactive nuclei in laminae IV–VI. Our results are the first demonstration of the presence of functional type 1a GHSRs in the spinal cord and indicate that ghrelin may exert antinociceptive effects by directly increasing inhibitory neurotransmission in a subset of deep dorsal horn neurons.