Adenosine and adenosine analogs induce analgesia in humans and presumed antinociception in animal models when administered both systemically and intrathecally. In the present investigation in rats, we studied the effects of intrathecally administered adenosine analogs, with or without systemic coadministration of an adenosine antagonist (theophylline), on substance P (SP) and calcitonin gene-related peptide (CGRP) concentrations in cerebrospinal fluid (CSF). In parallel, nociceptive reflex testing (tail immersion latency) and motor function were evaluated. The potent unselective adenosine receptor agonist N-ethylcarboxamide-adenosine (NECA) and the relatively adenosine A1 receptor selective agonist R-phenyl-isopropyl-adenosine (R-PIA) both reduced SP-like immunoreactivity (-LI) by 50%, whereas CGRP-LI remained unchanged. There was a dose-dependent increase in tail immersion latency. This effect was present without motor impairment when R-PIA was administered in doses up to 5 nmol. R-PIA (10-100 nmol), as well as 1-100 nmol of the unselective agonist NECA, produced dose-dependent motor impairment. The reduction of SP-LI as well as the behavioral effects were reversed by theophylline. We conclude that SP reduction in CSF, which possibly reflects reduced SP turnover after adenosine receptor stimulation, provides an additional possible mechanism of action for the analgesic effects of adenosine.
Implications: We studied the interactions between the known pain mediator substance P and substances with effects similar to the endogenous pain modulator adenosine in rats. The results suggest that the pain-reducing effect of adenosine is, at least partly, due to a reduction of substance P in cerebrospinal fluid.