Effect of endomorphin on somatostatin secretion in the isolated perfused rat stomach

Abstract

Recently the two peptides endomorphin-1 and −2 were isolated from bovine brain, which are postulated to be endogenous agonists for μ-opiate receptors in the CNS. Since exogenous and endogenous opioids have been shown to influence gastric functions, it was of interest to examine the effects of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and −2 (Tyr-Pro-Phe-Phe-NH2, EM-2) in the isolated perfused rat stomach. Results: EM-1 10−8M and 10−6M inhibited somatostatin (SLI) levels from a mean of 79 ± 2.7pg/min and 73 ± 2.7pg/min to 52 ± 4.0pg/min (n = 5, n.s.) and 27 ± 3.0pg/min (n = 5, P < 0.05), respectively. To characterize the effect on stimulated SLI-secretion, it was prestimulated for 30min with gastric inhibitory polypeptide (GIP, 10−9M). EM-1 decreased prestimulated SLI-secretion in a concentration-dependent manner from a mean of 469 ± 64.9pg/min during the immediately preceding 15 minutes to 184 ± 12.1pg/min (67 ± 4.0 %) at 10−7M and from a mean of 1146 ± 269.6pg/min to 111 ± 14.1pg/min (94 ± 2.2 %) at 10−6M (each n = 6, each P < 0.05). In addition EM-2 was also examined at a concentration of 10−6M, which inhibited prestimulated SLI-secretion from a mean of 514 ± 14.9pg/min to a nadir of 204 ± 44.7pg/min (42 ± 5 %, n = 6, P < 0.05). Application of the specific μ-opiate receptor antagonist CTOP in doses of 10−7 to 10−5M significantly attenuated the inhibitory effect of EM-1 10−7M from 67 ± 4.0 % to 34 ± 4.7 % (10−7M), 33 ± 3.0 % (10−6M) or 30 ± 8.6 % (10−5M), respectively. This residual inhibition, however, was still significantly different from the preceding perfusion period. On the other hand, naloxone 10−6M completely abolished the inhibitory effect of EM-1 10−7M. Similarly, the inhibitory effect of 10−6M EM-1 was also significantly reduced by CTOP from 94 ± 2.2 % to 60 ± 10.9 % (10−7M), 61 ± 5.5 % (10−6M) or 51 ± 12.5 % (10−5M), respectively, and the residual effect was significantly different from the preceding perfusion period as well. At this higher dose of EM-1 (10−6M) naloxone 10−6M reduced the effect to 35 ± 8.2 %, but there was still a significant difference of SLI levels compared to the preceding stimulation period (P < 0.05). Naloxone 10−6M reduced the inhibitory effect of EM-2 10−6M from 42 ± 5.0 % to 20 ± 5.0 % (P < 0.05), which was still significantly different compared to the preceding stimulation period. EM-1 at the doses of 10−12M, 10−10M, 10−8M and 10−6M had no significant effect neither on basal gastrin, bombesin (BLI) and vasoactive intestinal polypeptide (VIP) release nor during concomitant infusion of GIP. Conclusions: EM-1 and −2 inhibit basal and prestimulated SLI secretion in the isolated perfused rat stomach, which is in part attenuated by the μ-receptor antagonist CTOP. The greater inhibitory effect of naloxone, which can be demonstrated at least during the lower dose of EM-1, indicates that other opiate receptors contribute as well. The failure of naloxone to completely antagonize the effect of the higher concentration of EM-1 or EM-2 could be due to insufficient dosage or might indicate the involvement of non-opiate receptor mechanisms.