Allosteric adenosine modulation to reduce allodynia

Background: Adenosine and adenosine agonists reduce hypersensitivity following inflammation and peripheral nerve injury models of chronic pain. Because inhibitors of adenosine reuptake or metabolism are also effective at reducing hypersensitivity, it is likely that there is a tonic release of spinal adenosine in these models. One approach to avoid adverse effects from direct agonists is to enhance the effect of the endogenous ligand by administering a positive allosteric modulator of its receptor. Methods: Rats with mechanical hypersensitivity after spinal nerve ligation received intrathecal injections of adenosine, the allosteric adenosine receptor modulator T62, or their combination, or received systemic T62 alone or with intrathecal injection of a specific A1 adenosine antagonist. Results: Both adenosine and T62 reduced hypersensitivity alone, with 50% maximal doses (ED₅₀) of 14 ± 5.9 and 3.7 ± 0.8 μg, respectively. They interacted in an additive manner as determined by isobolography. T62 also reduced mechanical hypersensitivity after systemic administration (15 mg/kg), and this effect was blocked by intrathecal injection of 9 μg of the Al-specific adenosine receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine. Conclusions: These results add to previous studies that suggest ongoing spinal release of adenosine, which is antiallodynic, in this animal model of neuropathic pain. Positive allosteric modulation of the adenosine receptor reduces hypersensitivity by a spinal mechanism involving A1 adenosine receptor stimulation. Although obvious adverse effects were not observed in this investigation, further study is required to determine the feasibility of the use of such modulators in the treatment of chronic pain associated with hyperalgesia and allodynia.