In recent years there have been further significant

In recent years, there have been further significant developments that enhance an understanding of the role of adenosine in nociception. Thus, novel methods of recruiting adenosine A1Rs have been developed, and the role of adenosine A2A- and A3Rs in nociception has been further elaborated. Furthermore, a contribution of endogenous adenosine to the actions of several pharmacological agents, as well as non-pharmacological procedures, used to manage pain has been described. The focus of the present review is a current view relating to potential development of adenosine-based therapeutics as analgesics, and to contributions of endogenous adenosine systems to the efficacy of drugs and procedures used to manage chronic pain. Furthermore, pragmatic issues relating to the influence of caffeine on this therapeutic development are considered.
Adenosine A2ARs are expressed peripherally on inflammatory and immune cells, mediate a host of anti-inflammatory actions, and are considered as targets for inflammatory and immune conditions (Haskó et al., 2008, Antonioli et al., 2014). In the CNS, they are selectively expressed in certain CID 755673 regions, are located pre- and post synaptically on neurons, and are expressed on glia; neuroprotective effects occur with receptor manipulation, and A2ARs are considered as potential targets for several CNS disorders (e.g. Parkinson’s disease, Huntington’s disease, Alzheimer’s disease; following ischemia or spinal cord injury), although the optimal profile (agonist, antagonist) is not fully clear (Popoli and Pepponi, 2012, Antonioli et al., 2014). Localization on both neurons and glia are potentially relevant to pain, especially with the recognition of the contribution of glia (microglia, astrocytes) to sensitisation and chronic pain (Milligan and Watkins, 2009, Ji et al., 2013). A2ARs are present on glia, and may participate in regulating their function (Boison et al., 2010, Paterniti et al., 2011, Gomes et al., 2013).
In the periphery, A2BRs are present on immune and inflammatory cells, and activation results in potentiation of many inflammatory responses (Haskó et al., 2009, Feoktistov and Biaggioni, 2011). In the CNS and spinal cord, A2BRs occur at low levels, but expression on astrocytes is prominent (Popoli and Pepponi, 2012). Adenosine has a lower affinity for A2BRs than for other subtypes, and A2BRs may be more important when tissue levels of adenosine are elevated such as in hypoxia/ischemia and in inflammation (Fredholm et al., 2011). A2BR antagonists are being explored as potential therapeutics for immune and inflammatory disorders, but translation will require a better understanding of the multiple roles (anti- and pro-inflammatory actions) that occur in different tissues and at different stages of injury processes (Feoktistov and Biaggioni, 2011, Antonioli et al., 2014). There are a limited number of reports on the effects of A2BRs in nociception, reflecting the more recent characterization of this receptor, and initial lack of availability of highly selective agents. The first report noted that systemic administration of a series of A2BR antagonists resulted in antinociception in an acute nociceptive test; this action was attributed to a peripheral effect, as a peripherally restricted analog also exhibited activity (Abo-Salem et al., 2004). In a subsequent study, systemic administration of the selective A2BR antagonist PSB115 reduced nociceptive behaviors and edema following local injection of formalin, but it had variable effects following carrageenan (Bilkei-Gorzo et al., 2008). In general, these observations are consistent with a peripheral pronociceptive and proinflammatory profile for A2BRs. In other studies which focus on spinal administration of test agents, a selective A2BR antagonist (alloxazine) was able to reverse the antinociceptive action of i.t. adenosine in the formalin model of pain, suggesting an antinociceptive role for spinal A2BRs (Yoon et al., 2006). More recently, acute i.t. administration of the selective A2BR agonist BAY 606583 produced a long-lasting reversal of allodynia in the chronic constriction injury model, an effect similar to that seen with A2AR agonists (Loram et al., 2013). Given that both A2A- and A2BRs involve increased cyclic AMP generation and activation of downstream events, their spinal mechanisms of action were proposed to be similar (Loram et al., 2013). In general, A2BR activation leads to increased cyclic AMP, PKA activation and downstream events via Gαs, and activation of the PLC/IP3/DAG pathway and downstream events via Gαq, and altered gene transcription; the β-arrestin pathway mediates receptor internalization (Chen et al., 2014).