Validation of a preclinical spinal safety model: Effects of intrathecal morphine in the neonatal rat

B. David Westin, Suellen M. Walker, Ronald Deumens, Marjorie Grafe, Tony L. Yaksh

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Original languageEnglish (US)
Pages (from-to)183-199
Number of pages17
JournalAnesthesiology
Volume113
Issue number1
DOIs
StatePublished - Jul 2010

Fingerprint

Morphine
Safety
Spinal Injections
Spinal Cord
Analgesics
Sensory Thresholds
Poisons
Gait
Neuroglia
Analgesia
General Anesthesia
Apoptosis
Injections
Therapeutics

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Validation of a preclinical spinal safety model : Effects of intrathecal morphine in the neonatal rat. / Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

In: Anesthesiology, Vol. 113, No. 1, 07.2010, p. 183-199.

Research output: Contribution to journalArticle

Westin, B. David ; Walker, Suellen M. ; Deumens, Ronald ; Grafe, Marjorie ; Yaksh, Tony L. / Validation of a preclinical spinal safety model : Effects of intrathecal morphine in the neonatal rat. In: Anesthesiology. 2010 ; Vol. 113, No. 1. pp. 183-199.
@article{e0ef7bd48ed240b6a3851f3d6db4b795,
title = "Validation of a preclinical spinal safety model: Effects of intrathecal morphine in the neonatal rat",
abstract = "Background: Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.",
author = "Westin, {B. David} and Walker, {Suellen M.} and Ronald Deumens and Marjorie Grafe and Yaksh, {Tony L.}",
year = "2010",
month = "7",
doi = "10.1097/ALN.0b013e3181dcd6ec",
language = "English (US)",
volume = "113",
pages = "183--199",
journal = "Anesthesiology",
issn = "0003-3022",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Validation of a preclinical spinal safety model

T2 - Effects of intrathecal morphine in the neonatal rat

AU - Westin, B. David

AU - Walker, Suellen M.

AU - Deumens, Ronald

AU - Grafe, Marjorie

AU - Yaksh, Tony L.

PY - 2010/7

Y1 - 2010/7

N2 - Background: Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

AB - Background: Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

UR - http://www.scopus.com/inward/record.url?scp=77954177557&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954177557&partnerID=8YFLogxK

U2 - 10.1097/ALN.0b013e3181dcd6ec

DO - 10.1097/ALN.0b013e3181dcd6ec

M3 - Article

C2 - 20526189

AN - SCOPUS:77954177557

VL - 113

SP - 183

EP - 199

JO - Anesthesiology

JF - Anesthesiology

SN - 0003-3022

IS - 1

ER -