n(6)-cyclohexyladenosine and 5--amino-5--deoxyadenosine

The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 microl), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7-10 days prior to drug testing (antagonist experiments). N6-cyclohexyladenosine (CHA; adenosine A1 receptor agonist; 0.01-1 nmol), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine (CGS21680; adenosine A2A receptor agonist; 0.1-10 nmol), 5'-amino-5'-deoxyadenosine (NH2dAdo; adenosine kinase inhibitor: 10-300 nmol), and 5-iodotubercidin (ITU; adenosine kinase inhibitor; 0.1-100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2'-deoxycoformycin (dCF; an adenosine deaminase inhibitor; 100-300 nmol). Reversal of drug effects by caffeine (non-selective adenosine A1/A2 receptor antagonist; 515 nmol) confirmed the involvement of the adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; adenosine A2A receptor antagonist; 242 nmol), evidenced an adenosine A1 receptor mediated spinal antinociception by NH2dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH2dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting adenosine agents, when administered spinally, produce antinociception through activation of spinal adenosine A1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected adenosine kinase inhibitors can be significantly augmented when administered simultaneously with an adenosine deaminase inhibitor.

Topics: Adenosine; Adenosine Deaminase; Animals; Antihypertensive Agents; Carrageenan; Deoxyadenosines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Edema; Enzyme Inhibitors; Excipients; Hot Temperature; Hyperalgesia; Male; Neuritis; Neurons; Nociceptors; Pentostatin; Phenethylamines; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Tubercidin

Spinal administration of adenosine analogs and an adenosine kinase inhibitor produces antinociception in thermal threshold tests. In the present study, we determined the effects of N6-cyclohexyladenosine (adenosine A1 receptor selective), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethyl-carboxamidoadeno sine (CGS-21680) (adenosine A2A receptor selective), and 5'-N-ethylcarboxamidoadenosine (NECA) (non-selective), on formalin induced nociceptive responses (flinching/lifting and licking/biting) using two concentrations of formalin (2% and 5%). We also examined the antinociceptive effects of 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, and deoxycoformycin, an adenosine deaminase inhibitor, under these conditions. Adenosine A1 receptor agonists, but not the A2A selective agent, produced significant antinociception, as did 5'-amino-5'-deoxyadenosine, but not deoxycoformycin. The extent of antinociception produced was greater with the lower stimulus intensity. The effects of NECA and 5'-amino-5'-deoxyadenosine were inhibited by caffeine, indicating the involvement of cell surface adenosine receptors in their actions. We conclude (a) that the adenosine A1, but not the A2A, receptor is involved in spinally mediated antinociception, (b) that adenosine kinase is more important than adenosine deaminase in regulating endogenous adenosine levels in the spinal cord, and (c) that stimulus intensity is an important determinant of the efficacy of purines in the spinal cord.

Topics: Adenosine; Adenosine Kinase; Adenosine-5'-(N-ethylcarboxamide); Analgesics; Animals; Caffeine; Deoxyadenosines; Enzyme Inhibitors; Formaldehyde; Male; Pentostatin; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1