Preclinical toxicity screening of intrathecal adenosine in rats and dogs

Background: Intrathecally administered adenosine receptor agonists have ant inociceptive effects in animals, suggesting that intrathecal adenosine migh t provide analgesia in humans. The authors performed preclinical neurotoxic ity studies to define the safety of intrathecally administered adenosine in rats and dogs. Methods: Eighteen rats with long-term intrathecal catheters received daily injections of saline or 100 mu g adenosine for 4 days and were observed for general behavior and thermal nociception before being killed on day 6. Nin e beagle dogs were prepared with long-term, lumbar intrathecal catheters an d infused continuously with saline or adenosine, 2.4 mg/day for 48 h, then 7.2 mg/day for 26 days. Animals mere then anesthetized and perfused with pr eservative and their spinal cords were examined systematically. Results: No disturbances in neurologic function were detected in either ani mal species. intrathecal adenosine caused transient sedation in rats and in creased muscle tone in dogs, resolving with continued exposure to drug. Nei ther adenosine-nor saline-treated rats or dogs showed acute thermal analges ia. Adenosine groups did not differ from saline groups regarding histopatho logy, although a moderate fibrotic and inflammatory reaction was noted in b oth, and protein concentrations in cerebrospinal fluid were increased in bo th. Conclusion: The current study hi rats and dogs failed to provide behavioral or histologic evidence of neurotoxicity from intrathecal administration of adenosine. This provides evidence for the presumption of safety of adenosi ne in tills dose range, and supports phase I safety trials of acute intrath ecal adenosine administration in humans.