Preclinical toxicity screening of intrathecal oxytocin in rats and dogs

Tony L. Yaksh, Shotaro Hobo, Christopher Peters, Kent G. Osborn, Philip J. Richter, Steven S. Rossi, Marjorie Grafe, James C. Eisenach

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)951-961
Number of pages11
JournalAnesthesiology
Volume120
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Oxytocin
Dogs
Spinal Injections
Injections
Poisons
Pruritus
Chronic Pain
Analgesia
Neurotransmitter Agents
Spinal Cord
Heart Rate
Blood Pressure
Wounds and Injuries

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Yaksh, T. L., Hobo, S., Peters, C., Osborn, K. G., Richter, P. J., Rossi, S. S., ... Eisenach, J. C. (2014). Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. Anesthesiology, 120(4), 951-961. https://doi.org/10.1097/ALN.0000000000000148

Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. / Yaksh, Tony L.; Hobo, Shotaro; Peters, Christopher; Osborn, Kent G.; Richter, Philip J.; Rossi, Steven S.; Grafe, Marjorie; Eisenach, James C.

In: Anesthesiology, Vol. 120, No. 4, 2014, p. 951-961.

Research output: Contribution to journalArticle

Yaksh, TL, Hobo, S, Peters, C, Osborn, KG, Richter, PJ, Rossi, SS, Grafe, M & Eisenach, JC 2014, 'Preclinical toxicity screening of intrathecal oxytocin in rats and dogs', Anesthesiology, vol. 120, no. 4, pp. 951-961. https://doi.org/10.1097/ALN.0000000000000148
Yaksh TL, Hobo S, Peters C, Osborn KG, Richter PJ, Rossi SS et al. Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. Anesthesiology. 2014;120(4):951-961. https://doi.org/10.1097/ALN.0000000000000148
Yaksh, Tony L. ; Hobo, Shotaro ; Peters, Christopher ; Osborn, Kent G. ; Richter, Philip J. ; Rossi, Steven S. ; Grafe, Marjorie ; Eisenach, James C. / Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. In: Anesthesiology. 2014 ; Vol. 120, No. 4. pp. 951-961.
@article{e4e2c39f5d624fbbb1dbab5e702d509e,
title = "Preclinical toxicity screening of intrathecal oxytocin in rats and dogs",
abstract = "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.",
author = "Yaksh, {Tony L.} and Shotaro Hobo and Christopher Peters and Osborn, {Kent G.} and Richter, {Philip J.} and Rossi, {Steven S.} and Marjorie Grafe and Eisenach, {James C.}",
year = "2014",
doi = "10.1097/ALN.0000000000000148",
language = "English (US)",
volume = "120",
pages = "951--961",
journal = "Anesthesiology",
issn = "0003-3022",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Preclinical toxicity screening of intrathecal oxytocin in rats and dogs

AU - Yaksh, Tony L.

AU - Hobo, Shotaro

AU - Peters, Christopher

AU - Osborn, Kent G.

AU - Richter, Philip J.

AU - Rossi, Steven S.

AU - Grafe, Marjorie

AU - Eisenach, James C.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84901800581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901800581&partnerID=8YFLogxK

U2 - 10.1097/ALN.0000000000000148

DO - 10.1097/ALN.0000000000000148

M3 - Article

VL - 120

SP - 951

EP - 961

JO - Anesthesiology

JF - Anesthesiology

SN - 0003-3022

IS - 4

ER -