Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics

Abstract

Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A1 , A2A , A2B and A3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A1 and A2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A3 receptor is only in its infancy, but exciting preclinical observations of A3 receptor antinociception, which have been bolstered by clinical trials of A3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A3 receptor on pain pathways and examine the current state of selective A3 receptor agonists used for these studies. The adenosine-to-A3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain.

Figure 1

Adenosine synthesis and metabolism. ATP can be released from various cell types in response to cell excitation or insult. ATP can be deophosphorylated in sequence to form ADP, AMP and finally adenosine. In the extracellular space, ectonucleotidases (CD39 and CD73) facilitate formation of adenosine. Adenosine can act on its cognate receptors (A₁, A_2A, A_2B and A₃) or be removed from the extracellular space by metabolic enzymes (adenosine deaminase, ADA) or by transport back into the cell via equilibrative nucleoside transporters (ENTs) or concentrative nucleoside transporters (CNTs). In the intracellular space, adenosine can be converted to AMP (by adenosine kinase, ADK) which in turn is catalysed to ADP and then ATP. Intracellular adenosine can also be generated from AMP by 5′‐nucleotidase.

Figure 2

A₃ receptor's multiple sites of action. Studies employing selective A₃ receptor agonists have uncovered the efficacy of A₃ receptor activation at several sites important for pain processing. In the ascending pathway (red), a stimulus is conducted from the periphery to the spinal cord where it is then transported to the brain to be interpreted. The brain is able to modulate these events via the descending pathway (green). The i.d. administration of IB‐MECA (3–60 nmol; Salvemini unpublished results) dose‐dependently attenuated the reduction in paw withdrawal thresholds (PWTs) associated with chronic constriction injury (CCI). These results were extended by MRS5698 administration via surgically implanted catheters placed into the intrathecal (i.t.; 3–60 nmol) space or rostral ventromedial medulla (RVM; 0.3–3 nmol). Data are mean ± SD for n = 5 animals per group and analysed by two‐way ANOVA with Bonferroni comparisons. #P < 0.05 vs. D0; *P < 0.05 vs. D7. The i.t. data are reprinted with permission from J Neuro (Ford et al., 2015) . Intra‐RVM data are reprinted with permission from Brain (Little et al., 2015).

Figure 3

Potential mechanisms of A₃ receptor (A₃AR)‐mediated antinociception. Several pathways are known to be important in the establishment of pain states including impairment of GABAergic neurotransmission, enhanced neuroinflammation characterized by increased glial hyperactivation and TLR4 signalling, increased glutamatergic signalling and heightened production of nitroxidative species. The A₃ receptor has been shown to modulate these pathways through the use of selective agonists, potentially explaining A₃ receptor's antinociceptive actions.

Figure 4

Pharmacological agents useful for the study of A₃ receptor‐mediated antinociception. Preclinically useful selective A₃ receptor agonists (1–6), A₃ receptor antagonists (7–8) and adenosine modulators (9–12).