ici-154129 and deltakephalin

Opioid-cholecystokinin (CCK) interactions at the spinal level were investigated by looking for possible modulations by various opioid agonists of the release of cholecystokinin-like material (CCKLM) from slices of the dorsal zone of the rat lumbar enlargement. K(+)-evoked CCKLM overflow was reduced by 0.1-10 microM of the mu agonist DAGO or 10 nM to 3 microM of the delta agonist DTLET. By contrast, at a higer concentration (10 microM), the latter drug as well as morphine enhanced CCKLM overflow. Although inactive alone, the kappa opioid agonist U 50488 H (1 microM) prevented the inhibitory effect of DAGO without affecting that of DTLET. These data suggest that an opioid acting through the stimulation of mu, delta and kappa receptors (such as morphine) should produce a net increase in the spinal release of CCK.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Cholecystokinin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; In Vitro Techniques; Male; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord

Superfusion of slices from the dorsal half of the lumbar enlargement of rat spinal cord with Krebs-Henseleit medium supplemented with 30 microM bacitracin allowed the collection of substance P-like immunoreactive material (SPLI), which was released at a rate of approximately 10 pg/4 min. Tissue depolarization by an excess of K+ (30-60 mM) or veratridine (50 microM) induced a marked increase in SPLI outflow, provided that Ca2+ was present in the superfusing fluid. K+- or veratridine-induced SPLI overflow could be modulated in opposite directions by mu and delta opioid receptor agonists. Thus, the two preferential mu agonists Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO; 10 microM) and Tyr-D-Ala-Gly-MePhe-Met(O)5-OH (FK-33824; 0.1 microM) enhanced SPLI overflow from depolarized tissues, whereas the selective delta agonists Tyr-D-Thr-Gly-Phe-Leu-Thr (deltakephalin; 3 microM) and [2-D-penicillamine, 5-D-penicillamine]enkephalin (50 microM) reduced it. The effect of DAGO was antagonized by a low concentration (1 microM) of naloxone but not by the selective delta antagonist ICI-154129 (50 microM). In contrast, the latter drug prevented the inhibitory influence of delta agonists on K+-induced SPLI release. Complementary experiments with morphine (10 microM) and [2-D-alanine, 5-D-leucine]enkephalinamide (3 microM), in combination with 1 microM naloxone or 50 microM ICI-154129 for the selective blockade of mu or delta receptors, respectively, confirmed that the stimulation of mu receptors increased, whereas the stimulation of delta receptors reduced, SPLI overflow. The results suggest that, at the spinal level, and antinociceptive action of delta but not mu agonists might involve a presynaptic inhibition of substance P-containing primary afferent fibers.

Topics: Animals; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; In Vitro Techniques; Male; Morphine; Naloxone; Oligopeptides; Potassium; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord; Substance P; Tetrodotoxin; Veratridine