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. 2012 Oct;43(4):1751-9.
doi: 10.1007/s00726-012-1260-8. Epub 2012 Mar 10.

Pharmacological characterization of the ghrelin receptor mediating its inhibitory action on inflammatory pain in rats

Valeria Sibilia  1 , Francesca Pagani, Emanuela Mrak, Elisa Dieci, Giovanni Tulipano, Francesco Ferrucci
Affiliations

Pharmacological characterization of the ghrelin receptor mediating its inhibitory action on inflammatory pain in rats

Valeria Sibilia et al. Amino Acids. 2012 Oct.

Abstract

Recent research suggests a role for ghrelin in the modulation of inflammatory disorders. However, the type of ghrelin receptor (GHS-R) involved in both the anti-inflammatory and anti-hyperalgesic actions of ghrelin remains to be characterized. In this study, we examined whether the inhibitory effect of ghrelin in the development of hyperalgesia and edema induced by intraplantar carrageenan administration depends on an interaction with GHS-R1a. Both central (1 nmol/rat, i.c.v.) and peripheral (40 nmol/kg, i.p.) administration of the selective GHS-R1a agonist EP1572 had no effect on carrageenan-induced hyperalgesia measured by Randall-Selitto test and paw edema. Furthermore, pre-treatment with the selective GHS-R1a antagonist, D-lys(3)-GHRP-6 (3 nmol/rat, i.c.v.) failed to prevent the anti-hyperalgesic and anti-inflammatory effects exerted by central ghrelin administration (1 nmol/rat), thus indicating that the type 1a GHS-R is not involved in these peptide activities. Accordingly, both central (1 and 2 nmol/rat, i.c.v.) and peripheral (40 and 80 nmol/kg, i.p.) administration of desacyl-ghrelin (DAG), which did not bind GHS-R1a, induced a significant reduction of the hyperalgesic and edematous activities of carrageenan. In conclusion, we have shown for the first time that DAG shares with ghrelin an inhibitory role in the development of hyperalgesia, as well as the paw edema induced by carrageenan and that a ghrelin receptor different from type 1a is involved in the anti-inflammatory activities of the peptide.

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Figures

Fig. 1
Fig. 1
Effect of intracerebroventricular (i.c.v.) injection of EP1572 on hyperalgesia (a) and paw edema (b) induced by carrageenan. EP1572 was administered 5 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 10–12 rats. **P < 0.001 versus basal
Fig. 2
Fig. 2
Effect of peripheral (i.p.) injection of EP1572 on hyperalgesia (a) and paw edema (b) induced by carrageenan. EP1572 was administered 30 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 10–12 rats. **P < 0.001 versus basal
Fig. 3
Fig. 3
Effect of pretreatment (5 min before) with d-lys3-GHRP-6 on the inhibitory action of ghrelin on hyperalgesia (a) and paw edema (b) induced by i.pl. carrageenan. Ghrelin was injected i.c.v. 5 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 12–14 rats. **P < 0.001 versus basal; •• P < 0.01, ••• P < 0.001 versus saline; # P < 0.05 versus ghrelin
Fig. 4
Fig. 4
Effect of intracerebroventricular (i.c.v.) injection of d-lys3-GHRP-6 on the inhibitory action of ghrelin on hyperalgesia (a) and paw edema (b) induced by i.pl. carrageenan. d-Lys3-GHRP-6 was injected 5 min before ghrelin and 135 min after carrageenan. Ghrelin was injected i.c.v. 5 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 6–8 rats. **P < 0.001 versus basal; •• P < 0.01, ••• P < 0.001 versus saline; # P < 0.05 versus ghrelin
Fig. 5
Fig. 5
Effect of intracerebroventricular (i.c.v.) injection of desacyl-ghrelin (DAG) on hyperalgesia (a) and paw edema (b) induced by carrageenan. DAG was administered 5 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 10–12 rats. *P < 0.05, **P < 0.001 versus basal; • P < 0.05, •• P < 0.01, ••• P < 0.001 versus saline
Fig. 6
Fig. 6
Effect of peripheral (i.p.) injection of desacyl-ghrelin (DAG) on hyperalgesia (a) and paw edema (b) induced by carrageenan. DAG was administered 30 min before i.pl. carrageenan. Paw pressure threshold and paw volume were measured prior to carrageenan (basal) and at various times after carrageenan. Each value is the mean ± SEM of 10–12 rats. **P < 0.001 versus basal; • P < 0.05, •• P < 0.01 versus saline
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