Preclinical toxicity screening of intrathecal oxytocin in rats and dogs.
BACKGROUND
Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. In this article, the authors report preclinical toxicity screening of oxytocin for intrathecal delivery.


METHODS
Intrathecal oxytocin, 11 μg (6 U) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In three dogs, a range of intrathecal oxytocin doses (18 to 550 μg in 0.5 ml) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive five daily injections of intrathecal oxytocin, 550 μg in 0.5 ml, or vehicle with similar assessments and, necropsy and histologic analysis were conducted 2 days later.


RESULTS
In rats, intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose ranging in dogs suggested mild effects on motor tone, blood pressure, and heart rate at the 550 μg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity.


CONCLUSIONS
Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1,100 μg/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision.
From the Department of Anesthesiology, University of California, San Diego, San Diego, California (T.L.Y.); Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina (S.H., C.P., and J.C.E.); Diagnostic Laboratory, Animal Care Program, University of California, San Diego, San Diego, California (K.G.O.); Animal Care Program, Department of Pathology, University of California, San Diego, San Diego, California (P.J.R.); Anesthesiology Research Laboratory, University of California, San Diego, San Diego, California (S.S.R.); and Department of Pathology, Neuropathology Oregon Health Sciences University, Portland, Oregon (M.R.G.).
Tony L
TL
Yaksh
Shotaro
S
Hobo
Christopher
C
Peters
Kent G
KG
Osborn
Philip J
PJ
Richter
Steven S
SS
Rossi
Marjorie R
MR
Grafe
James C
JC
Eisenach
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D007278:Injections, Spinal; D008297:Male; D010120:Oxytocics / Q000008:administration & dosage / Q000633:toxicity*; D010121:Oxytocin / Q000008:administration & dosage / Q000633:toxicity*; D011537:Pruritus / Q000139:chemically induced; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
D010120:Oxytocics; D010121:Oxytocin