INTRATHECAL ADENOSINE ANALOG ADMINISTRATION REDUCES SUBSTANCE-P IN CEREBROSPINAL-FLUID ALONG WITH BEHAVIORAL-EFFECTS THAT SUGGEST ANTINOCICEPTION IN RATS

Adenosine and adenosine analogs induce analgesia in humans and presume d antinociception in animal models when administered both systemically and intrathecally. In the present investigation in rats, we studied t he effects of intrathecally administered adenosine analogs, with or wi thout systemic coadministration of an adenosine antagonist (theophylli ne), on substance P (SP) and calcitonin gene-related peptide (CGRP) co ncentrations in cerebrospinal fluid (CSF). In parallel, nociceptive re flex testing (tail immersion latency) and motor function were evaluate d. The potent unselective adenosine receptor agonist N-ethylcarboxamid e-adenosine (NECA) and the relatively adenosine A(1) receptor selectiv e agonist R-phenylisopropyl-adenosine (R-PIA) both reduced SP-like imm unoreactivity (-LI) by 50%, whereas CGRP-LI remained unchanged. There was a dose-dependent increase in tail immersion latency. This effect w as present without motor impairment when R-PIA was administered in dos es up to 5 nmol. R-PIA (10-100 nmol), as well as 1-100 nmol of the uns elective agonist NECA, produced dose-dependent motor impairment. The r eduction of SP-LI as well as the behavioral effects were reversed by t heophylline. We conclude that SP reduction in CSF, which possibly refl ects reduced SF turnover after adenosine receptor stimulation, provide s an additional possible mechanism of action for the analgesic effects of adenosine. Implications: We studied the interactions between the k nown pain mediator substance P and substances with effects similar to the endogenous pain modulator adenosine in rats. The results suggest t hat the pain-reducing effect of adenosine is, at least partly, due to a seduction of substance P in cerebrospinal fluid.