Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.
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.
Westin
B David
BD
Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA.
Walker
Suellen M
SM
Deumens
Ronald
R
Grafe
Marjorie
M
Yaksh
Tony L
TL
D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005684:Gait / Q000187:drug effects; D007278:Injections, Spinal; D008297:Male; D023421:Models, Animal; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013116:Spinal Cord / Q000187:drug effects*
D000701:Analgesics, Opioid; D009020:Morphine