5--amino-5--deoxyadenosine and Pain

Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions.

Topics: Adenosine; Analgesics, Opioid; Animals; Deoxyadenosines; Dipyridamole; Drug Synergism; Injections, Spinal; Ligation; Male; Morphine; Neuritis; Pain; Pain Measurement; Physical Stimulation; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Spinal Nerves

Spinal administration of an adenosine kinase inhibitor, alone or in combination with an adenosine deaminase inhibitor, produces antinociception in inflammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) administration of 5'-amino-5'-deoxyadenosine (an adenosine kinase inhibitor), 2'-deoxycoformycin (an adenosine deaminase inhibitor), and combinations of both agents in the carrageenan-induced thermal hyperalgesia and paw oedema model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 micromol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinociceptive and anti-inflammatory effects was seen when 5'-amino-5'-deoxyadenosine and 2'-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of adenosine receptors, as indicated by blockade by an adenosine receptor antagonist. When administered into the contralateral paw, 1 micromol 5'-amino-5'-deoxyadenosine+1 micromol 2'-deoxycoformycin produced prominent antinociception, indicating a systemic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activity was locally mediated. Reversal of systemic effects on thermal thresholds by an intrathecal adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 micromol 5'-amino-5'-deoxyadenosine, but not 1 micromol 2'-deoxycoformycin, reduced carrageenan-induced c-Fos expression in the spinal dorsal horn, and this was further reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a predominantly peripheral anti-inflammatory effect produced by inhibitors of adenosine kinase and adenosine deaminase.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Adenosine Kinase; Analgesics; Animals; Anti-Inflammatory Agents; Caffeine; Carrageenan; Central Nervous System Stimulants; Deoxyadenosines; Dose-Response Relationship, Drug; Drug Synergism; Edema; Enzyme Inhibitors; Hindlimb; Hyperalgesia; Injections, Spinal; Male; Nociceptors; Pain; Pentostatin; Proto-Oncogene Proteins c-fos; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Spinal Cord; Theobromine; Time Factors

This study examined the ability of an adenosine kinase inhibitor (5'-amino-5'-deoxyadenosine; NH2dAD), an adenosine deaminase inhibitor (2'-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1-100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of adenosine and activation of cell surface adenosine receptors as it was blocked by the adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an inhibitory tone of adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2'-Deoxycoformycin 0.1-100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the adenosine kinase and deaminase inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous adenosine which accumulates following the peripheral inhibition of adenosine kinase; this action is due to activation of an adenosine A1 receptor.

Topics: Adenosine Deaminase Inhibitors; Adenosine Kinase; Animals; Deoxyadenosines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Injections, Subcutaneous; Male; Pain; Pain Measurement; Pentostatin; Rats; Rats, Sprague-Dawley

Adenosine or adenosine analogs injected intrathecally (i.t.) induce significant antinociception. Recent studies support the existence of an endogenous spinal system that can modulate nociceptive input by releasing adenosine. Inhibition of adenosine metabolism by administration of an adenosine kinase inhibitor, in the present study, decreased behavior induced by putative pain neurotransmitters providing additional support for an endogenous purinergic system. Conversely, administration of high doses of methylxanthines (i.t.), adenosine receptor antagonists, induced behavior similar to that induced by pain neurotransmitters. Methylxanthine (i.t.)-induced behavior was partially inhibited by antagonists of receptors for pain neurotransmitters. These observations are consistent with the hypothesis that an endogenous purinergic system tonically modulates nociceptive input involving a variety of chemical mediators. Preliminary studies also revealed methylxanthine-induced allodynia and suggested spinal purinergic systems may have a broader role in discriminating sensory input.

Topics: Adenosine; Animals; Deoxyadenosines; Grooming; Male; Mice; Neurotransmitter Agents; Pain; Spinal Cord; Substance P; Theophylline