Adenosine as a Potential Analgesic Target in Inflammatory and Neuropathic Pains

Substantial evidence exists for the physiological role of adenosine in the modulation of primary afferent transmission. Since the first description of the anti-nociceptive effects of adenosine, there has been considerable interest in the development of adenosine analogues as potential analgesics for the treatment of various pain states. The direction of effect of adenosine in the periphery is complicated by the existence of multiple receptors and species differences. The analgesic actions of agents acting on adenosine receptor systems are largely attributed to actions at the spinal cord. Two subtypes of adenosine receptors (A₁ and A₂) have been identified in the substantia gelatinosa of the spinal cord where they were shown to be localised primarily on intrinsic neurons. Although evidence exists for the involvement of A₂ receptors in spinally mediated antinociception, it appears to be predominantly the A₁ receptor subtype which plays a major role in inhibiting the nociceptive input in the dorsal spinal cord.

The antinociceptive properties of adenosine and receptor-selective analogues have been demonstrated across a wide range of animal models, including acute nociceptive tests and in models of inflammation and neuropathy. These results, observed across several models of pain, strongly support the potential clinical use of these agents in various pain states. In humans, systemic or intrathecal administration of adenosine was shown to be effective against experimentally induced pain in healthy volunteers. Subsequently, there is evidence for the effectiveness of systemic and spinally administered adenosine in patients with neuropathic pain.