Roles of Mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse

Frank Porreca, H. I. Mosberg, R. Hurst, Victor J Hruby, T. F. Burks

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Abstract

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 languageEnglish (US)
Pages (from-to)341-348
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume230
Issue number2
StatePublished - 1984

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D-Penicillamine (2,5)-Enkephalin
Gastrointestinal Transit
(trans)-Isomer 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide
kappa Opioid Receptor
delta Opioid Receptor
mu Opioid Receptor
Analgesia
Enkephalins
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Morphine
Analgesics
Benzeneacetamides
Opioid Receptors
Opioid Analgesics
Spinal Cord
Hot Temperature

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Roles of Mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse",
abstract = "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.",
author = "Frank Porreca and Mosberg, {H. I.} and R. Hurst and Hruby, {Victor J} and Burks, {T. F.}",
year = "1984",
language = "English (US)",
volume = "230",
pages = "341--348",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Roles of Mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse

AU - Porreca, Frank

AU - Mosberg, H. I.

AU - Hurst, R.

AU - Hruby, Victor J

AU - Burks, T. F.

PY - 1984

Y1 - 1984

N2 - 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.

AB - 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.

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