Preclinical Toxicity Screening of Intrathecal Oxytocin in Rats and Dogs

被引:21
作者
Yaksh, Tony L. [1 ]
Hobo, Shotaro [2 ]
Peters, Christopher [2 ]
Osborn, Kent G. [3 ]
Richter, Philip J., Jr. [4 ]
Rossi, Steven S. [5 ]
Grafe, Marjorie R. [6 ]
Eisenach, James C. [2 ]
机构
[1] Univ Calif San Diego, Dept Anesthesiol, San Diego, CA 92103 USA
[2] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC USA
[3] Univ Calif San Diego, Diagnost Lab, Anim Care Program, San Diego, CA 92103 USA
[4] Univ Calif San Diego, Dept Pathol, Anim Care Program, San Diego, CA 92103 USA
[5] Univ Calif San Diego, Anesthesiol Res Lab, San Diego, CA 92103 USA
[6] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR USA
关键词
QT INTERVAL PROLONGATION; SPINAL-CORD; CEREBROSPINAL-FLUID; NEOSTIGMINE METHYLSULFATE; ELECTRICAL-STIMULATION; SAFETY; ANTINOCICEPTION; TOXICOLOGY; PLASMA; PHARMACOLOGY;
D O I
10.1097/ALN.0000000000000148
中图分类号
R614 [麻醉学];
学科分类号
100217 [麻醉学];
摘要
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 g (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 g 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 g 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 g 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 g/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision.
引用
收藏
页码:951 / 961
页数:11
相关论文
共 39 条
[1]
Antinociceptive action of oxytocin involves inhibition of potassium channel currents in lamina II neurons of the rat spinal cord [J].
Breton, Jean Didier ;
Poisbeau, Pierrick ;
Darbon, Pascal .
MOLECULAR PAIN, 2009, 5
[2]
Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition [J].
Breton, Jean-Didier ;
Veinante, Pierre ;
Uhl-Bronner, Sandra ;
Vergnano, Angela Maria ;
Freund-Mercier, Marie Jose ;
Schlichter, Remy ;
Poisbeau, Pierrick .
MOLECULAR PAIN, 2008, 4
[3]
INTRATHECAL DYNORPHIN(1-13) RESULTS IN AN IRREVERSIBLE LOSS OF THE TAIL-FLICK REFLEX IN RATS [J].
CAUDLE, RM ;
ISAAC, L .
BRAIN RESEARCH, 1987, 435 (1-2) :1-6
[4]
QT interval prolongation after oxytocin bolus during surgical induced abortion [J].
Charbit, B ;
Funck-Brentano, C ;
Samain, E ;
Jannier-Guillou, V ;
Albaladejo, P ;
Marty, J .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2004, 76 (04) :359-364
[5]
Preclinical toxicity screening of intrathecal adenosine in rats and dogs [J].
Chiari, A ;
Yaksh, TL ;
Myers, RR ;
Provencher, J ;
Moore, L ;
Lee, CS ;
Eisenach, JC .
ANESTHESIOLOGY, 1999, 91 (03) :824-832
[6]
Oxytocin actions on afferent evoked spinal cord neuronal activities in neuropathic but not in normal rats [J].
Condés-Lara, M ;
Maie, IAS ;
Dickenson, AH .
BRAIN RESEARCH, 2005, 1045 (1-2) :124-133
[7]
Branched oxytocinergic innervations from the paraventricular hypothalamic nuclei to superficial layers in the spinal cord [J].
Condes-Lara, Miguel ;
Martinez-Lorenzana, Guadalupe ;
Rojas-Piloni, Gerardo ;
Rodriguez-Jimenez, Javier .
BRAIN RESEARCH, 2007, 1160 :20-29
[8]
Paraventricular oxytocinergic hypothalamic prevention or interruption of long-term potentiation in dorsal horn nociceptive neurons: Electrophysiological and behavioral evidence [J].
DeLaTorre, Salvador ;
Rojas-Piloni, Gerardo ;
Martinez-Lorenzana, Guadalupe ;
Rodriguez-Jimenez, Javier ;
Villanueva, Luis ;
Condes-Lara, Miguel .
PAIN, 2009, 144 (03) :320-328
[9]
Resolution of Pain after Childbirth [J].
Eisenach, James C. ;
Pan, Peter ;
Smiley, Richard M. ;
Lavand'homme, Patricia ;
Landau, Ruth ;
Houle, Timothy T. .
ANESTHESIOLOGY, 2013, 118 (01) :143-151
[10]
Safety in numbers: How do we study toxicity of spinal analgesics? [J].
Eisenach, JC ;
Yaksh, TL .
ANESTHESIOLOGY, 2002, 97 (05) :1047-1049