Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat

Craig Stevens, T. L. Yaksh

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

To determine the cross tolerance to the antinociceptive effects of μ and δ opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5- enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 μl/h), constant- dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused. At the infusion dose of 6 nmol/h for either morphine or DADLE, the shift of the cross-tolerance curve for DADLE in morphine-tolerant rats was only 2.7-fold, whereas that of morphine in DADLE-tolerant rats was only 1.3-fold. These data are interpreted as supporting separate sites of spinal antinociceptive action for morphine and DADLE in the rat and emphasize the importance of a dose-dependent induction and assessment of tolerance in studies of tolerance and cross-tolerance.

Original languageEnglish
Pages (from-to)596-603
Number of pages8
JournalAnesthesiology
Volume76
Issue number4
DOIs
StatePublished - 1 Jan 1992

Fingerprint

Morphine
Ala(2)-enkephalinamide-met
Infusion Pumps
Opioid Analgesics
Spinal Cord
Injections
Pharmaceutical Preparations

Keywords

  • Analgesics, intrathecal: cross-tolerance; morphine; tolerance
  • Brain: DADLE; Enkephalin
  • Receptors: opioid

Cite this

@article{d122e7c837f24b6f811f9c5496828080,
title = "Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat",
abstract = "To determine the cross tolerance to the antinociceptive effects of μ and δ opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5- enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 μl/h), constant- dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused. At the infusion dose of 6 nmol/h for either morphine or DADLE, the shift of the cross-tolerance curve for DADLE in morphine-tolerant rats was only 2.7-fold, whereas that of morphine in DADLE-tolerant rats was only 1.3-fold. These data are interpreted as supporting separate sites of spinal antinociceptive action for morphine and DADLE in the rat and emphasize the importance of a dose-dependent induction and assessment of tolerance in studies of tolerance and cross-tolerance.",
keywords = "Analgesics, intrathecal: cross-tolerance; morphine; tolerance, Brain: DADLE; Enkephalin, Receptors: opioid",
author = "Craig Stevens and Yaksh, {T. L.}",
year = "1992",
month = "1",
day = "1",
doi = "10.1097/00000542-199204000-00017",
language = "English",
volume = "76",
pages = "596--603",
journal = "Anesthesiology",
issn = "0003-3022",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "4",

}

Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat. / Stevens, Craig; Yaksh, T. L.

In: Anesthesiology, Vol. 76, No. 4, 01.01.1992, p. 596-603.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Studies of morphine and D-ala2-D-leu5-enkephalin (DADLE) cross-tolerance after continuous intrathecal infusion in the rat

AU - Stevens, Craig

AU - Yaksh, T. L.

PY - 1992/1/1

Y1 - 1992/1/1

N2 - To determine the cross tolerance to the antinociceptive effects of μ and δ opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5- enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 μl/h), constant- dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused. At the infusion dose of 6 nmol/h for either morphine or DADLE, the shift of the cross-tolerance curve for DADLE in morphine-tolerant rats was only 2.7-fold, whereas that of morphine in DADLE-tolerant rats was only 1.3-fold. These data are interpreted as supporting separate sites of spinal antinociceptive action for morphine and DADLE in the rat and emphasize the importance of a dose-dependent induction and assessment of tolerance in studies of tolerance and cross-tolerance.

AB - To determine the cross tolerance to the antinociceptive effects of μ and δ opioids in the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5- enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 μl/h), constant- dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose-response curves in DADLE-tolerant animals and DADLE dose-response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose-response curves was 55- and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose-response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose-response curves of animals tested with the same agent as infused. At the infusion dose of 6 nmol/h for either morphine or DADLE, the shift of the cross-tolerance curve for DADLE in morphine-tolerant rats was only 2.7-fold, whereas that of morphine in DADLE-tolerant rats was only 1.3-fold. These data are interpreted as supporting separate sites of spinal antinociceptive action for morphine and DADLE in the rat and emphasize the importance of a dose-dependent induction and assessment of tolerance in studies of tolerance and cross-tolerance.

KW - Analgesics, intrathecal: cross-tolerance; morphine; tolerance

KW - Brain: DADLE; Enkephalin

KW - Receptors: opioid

UR - http://www.scopus.com/inward/record.url?scp=0026559910&partnerID=8YFLogxK

U2 - 10.1097/00000542-199204000-00017

DO - 10.1097/00000542-199204000-00017

M3 - Article

C2 - 1550284

AN - SCOPUS:0026559910

VL - 76

SP - 596

EP - 603

JO - Anesthesiology

JF - Anesthesiology

SN - 0003-3022

IS - 4

ER -