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Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In normal animals, both ghrelin and its synthetic peptide, growth hormone releasing peptide 6 (GHRP-6), increase gastric emptying. Thus, we investigated the potential therapeutic significance of ghrelin and GHRP-6 in diabetic guinea pigs with gastric motility disorders. A diabetic guinea pig model was produced by intraperitoneal (i.p.) injection of streptozotocin (STZ, 280 mg/kg). Diabetic guinea pigs were injected i.p. with ghrelin or GHRP-6 (10 - 100 microg/kg), and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine or a growth hormone secretagogue receptor (GHS-R) antagonist, D-Lys(3)-GHRP-6, on the gastroprokinetic effects of ghrelin or GHRP-6 (100 microg/kg) was also investigated. Further, the in vitro effects of ghrelin or GHRP-6 (0.01 - 10 micromol/L) on spontaneous or carbachol-induced contractile amplitude in gastric fundic circular strips taken from diabetic guinea pigs were examined. Growth hormone secretagogue receptor transcripts in the fundic strips of diabetic guinea pigs were detected by reverse transcriptase polymerase chain reaction (RT-PCR). We established a guinea pig model of delayed gastric emptying. Ghrelin (20, 50, or 100 microg/kg) and GHRP-6 (20, 50, or 100 microg/kg) accelerated gastric emptying in diabetic guinea pigs with gastroparesis (n = 6, P < 0.05). In the presence of atropine, which delayed gastric emptying, ghrelin and GHRP-6 (100 microg/kg) failed to accelerate gastric emptying (n = 6, P < 0.05). D-Lys(3)-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist (n = 6, P < 0.05). Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundic strips taken from diabetic guinea pigs (n = 6, P < 0.05). RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. Ghrelin and GHRP-6 increased gastric emptying in diabetic guinea pigs with gastroparesis, potentially, by activating the peripheral cholinergic pathways in the enteric nervous system.