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

UNLABELLED: Recently the two peptides endomorphin-1 and -2 were isolated from bovine brain, which are postulated to be endogenous agonists for mu-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-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) in the isolated perfused rat stomach.

RESULTS: EM-1 10(-8) M and 10(-6) M inhibited somatostatin (SLI) levels from a mean of 79 +/- 2.7 pg/min and 73 +/- 2.7 pg/min to 52 +/- 4.0 pg/min (n = 5, n.s.) and 27 +/- 3.0 pg/min (n = 5, P < 0.05), respectively. To characterize the effect on stimulated SLI-secretion, it was prestimulated for 30 min with gastric inhibitory polypeptide (GIP, 10(-9) M). EM-1 decreased prestimulated SLI-secretion in a concentration-dependent manner from a mean of 469 +/- 64.9 pg/min during the immediately preceding 15 minutes to 184 +/- 12.1 pg/min (67 +/- 4.0 %) at 10(-7) M and from a mean of 1146 +/- 269.6 pg/min to 111 +/- 14.1 pg/min (94 +/- 2.2 %) at 10(-6) M (each n = 6, each P < 0.05). In addition EM-2 was also examined at a concentration of 10(-6) M, which inhibited prestimulated SLI-secretion from a mean of 514 +/- 14.9 pg/min to a nadir of 204 +/- 44.7 pg/min (42 +/- 5 %, n = 6, P < 0.05). Application of the specific mu-opiate receptor antagonist CTOP in doses of 10(-7) to 10(-5) M significantly attenuated the inhibitory effect of EM-1 10(-7) M from 67 +/- 4.0 % to 34 +/- 4.7 % (10(-7) M), 33 +/- 3.0 % (10(-6) M) or 30 +/- 8.6 % (10(-5) M), respectively. This residual inhibition, however, was still significantly different from the preceding perfusion period. On the other hand, naloxone 10(-6) M completely abolished the inhibitory effect of EM-1 10(-7) M. Similarly, the inhibitory effect of 10(-6) M EM-1 was also significantly reduced by CTOP from 94 +/- 2.2 % to 60 +/- 10.9 % (10(-7) M), 61 +/- 5.5 % (10(-6) M) or 51 +/- 12.5 % (10(-5) M), respectively, and the residual effect was significantly different from the preceding perfusion period as well. At this higher dose of EM-1 (10(-6) M) naloxone 10(-6) M 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(-6) M reduced the inhibitory effect of EM-2 10(-6) M 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(-12) M, 10(-10) M, 10(-8) M and 10(-6) M 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 mu-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.