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Adenosine as a Potential Analgesic Target in Inflammatory and Neuropathic Pains

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Abstract

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.

A number of studies have demonstrated possible interactions between adenosine and glutamate in the spinal cord, and between N-methyl-D-aspartate receptor activation and adenosine release elsewhere in the brain. There is also some evidence that drugs acting to inhibit the metabolism of adenosine may have therapeutic potential in pain states. In this context, the release of adenosine appears to be elevated in hyperexcitable neuronal systems. This would allow therapies to selectively target active neurons in pain systems and therefore would be expected to have low adverse effect liability.

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  1. Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Anthony H. Dickenson, Rie Suzuki & Alison J. Reeve

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Dickenson, A.H., Suzuki, R. & Reeve, A.J. Adenosine as a Potential Analgesic Target in Inflammatory and Neuropathic Pains. Mol Diag Ther 13, 77–85 (2000). https://doi.org/10.2165/00023210-200013020-00001

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