ROLES OF MU-RECEPTORS, DELTA-RECEPTORS AND KAPPA-OPIOID RECEPTORS IN SPINAL AND SUPRASPINAL MEDIATION OF GASTROINTESTINAL TRANSIT EFFECTS AND HOT-PLATE ANALGESIA IN THE MOUSE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 230  (2) , 341-348
Abstract
The opioid receptors involved in the mediation of thermal analgesia (55.degree. C hot-plate) and inhibition of gastrointestinal trasit at the spinal and supraspinal levels were studied in unanesthetized mice. Receptor-selective compounds (5) were evaluated for effectiveness in eliciting analgesia and inhibiting transit after both i.c.v. (intracerebroventricular) and in trathecal 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) and the nonselective mu-acting agonist, morphine. All compounds 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 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 from 20-40 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, and 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-50,448H. The use of the most seletive opioid agonists for the mu, delta and kappa receptors currently available along with 2 endpoints and administration sites suggests that in mice 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; hot-plate analgesia at the spinal cord level is mediated mainly by delta receptors while inhibition of transit is mediated through delta and mu receptors.