The opioid receptors involved in the mediation of thermal analgesia (55°C hot-plate) and inhibition of gastrointestinal transit at the spinal and supraspinal levels were studied in unanesthetized mice. Five receptor-selective compounds were evaluated for effectiveness in eliciting analgesia and inhibiting transit after both i.c.v. and intrathecal administration; these included the proposed mu agonist, [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAGO), the proposed delta agonists, [D-Pen2, L-Pen5]enkephalin (DPLPE), [D-Pen2, D-Pen5]enkephalin (DPDPE) (conformationally constrained delta selective enkephalin analogs) and [D-Thr2, Thr6, Leu5]enkephalin (DTTLE), and the proposed kappa agonist, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate (U-50,488H), as well as the nonselective mu-acting agonist, morphine. All compound were found to produce analgesia after i.c.v. administration; the rank order of potency by the i.c.v. route was DAGO > DTTLE > morphine > DPLPE > DPDPE > U-50,488H. The analgesic effectiveness of most of these agonists given i.c.v. was evident for up to 40 min, with only DTTLE and U-50,488H having briefer time courses. Similarly, all the compounds produced analgesic responses after intrathecal administration, with the rank order of potency by this route being DTTLE > morphine > DAGO > DPLPE > DPDPE > U-50,488H, and all compounds (except U-50,488H) had durations of action of up to 20 to 40 min. These agonists also inhibited gastrointestinal transit after intrathecal administration, with a rank order of potency of DAGO > DTTLE > DPLPE > morphine > DPDPE > U-50,488H. In contrast, the most selective agonists for the delta receptor, DPLPE and DPDPE, as well as the selective kappa agonist, U-50,488H, were ineffective against transit after i.c.v. administration; the i.c.v. rank potency for inhibition of transit was DAGO > DTTLE > morphine > DPLPE, DPDPE, U-50,488H. The use of the most selective opioid agonists for the mu, delta and kappa receptors currently available along with two endpoints and sites of administration suggests that in mice 1) hot-plate analgesia at the supraspinal level is mediated by both mu and delta receptors while antitransit effects at this site are mediated exclusively by mu receptors, and 2) hot-plate analgesia at the level of the spinal cord is mediated mainly by delta receptors while inhibition of transit is mediated through delta and mu receptors.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Oct 11 1984|
ASJC Scopus subject areas
- Molecular Medicine