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 (A 1 , A 2A , A 2B and A 3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A 1 and A 2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A 3 receptor is only in its infancy, but exciting preclinical observations of A 3 receptor antinociception, which have been bolstered by clinical trials of A 3 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 A 3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A 3 receptor on pain pathways and examine the current state of selective A 3 receptor agonists used for these studies. The adenosine-to-A 3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain. AbbreviationsADA, adenosine deaminase; ADK, adenosine kinase; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; CPP, conditioned place preference; ENT, equilibrative nucleoside transporter; PN, peroxynitrite; RVM, rostral ventromedial medulla; SO, superoxide; TLR4, toll-like receptor 4 BJP IntroductionChronic pain afflicts an estimated 10% of the world's adult population (Goldberg and McGee, 2011). The current therapeutic approaches for chronic pain include but are not limited to the use of nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants and opioid pain relievers; however, these strategies are frequently either inadequate or are associated with side effects that reduce quality of life or result in the discontinuation of therapy (Goldberg and McGee, 2011;Pizzo and Clark, 2012). The search for new therapeutic targets is therefore of great importance. Adenosine and two of its associated adenosine receptor subtypes, the A 1 and the A 2A receptor, have been investigated in the field of pain with varying degrees of success; however, these agents lack a useful therapeutic index due to cardiovascular side effects. In response, the focus of research has turned to the previously overlooked A 3 receptor, which displays both preclinical antinociceptive properties (Yoon et al., 2004;Janes et al., 2014bJanes et al., , 2015Ford et al., 2015;Little et al., 2015) and, in trials for non-pain conditions including psoriasis, hepatitis, rheumatoid arthritis, and glaucoma, offers a therapeutic index and tolerability that would be suitable for ...

Etiology and Pharmacology of Neuropathic Pain

“…Adenosine A3 receptor agonists represent one such class of agents as they interact with several of the pathophysiological mechanisms outlined above (Janes et al, 2016). A3 receptors are found on immune cells, astrocytes (Bjorklund et al, 2008;Janes et al, 2015), microglia (Hammarberg et al, 2003), and both peripheral and central neurons (Janes et al, 2016).…”

“…A3 receptors are found on immune cells, astrocytes (Bjorklund et al, 2008;Janes et al, 2015), microglia (Hammarberg et al, 2003), and both peripheral and central neurons (Janes et al, 2016). In addition, the A3 receptor agonist MRS5698 attenuates KCC2 downregulation and restores Cl 2 gradients in rodent CCI models , a process that may involve attenuation of BDNF signaling (Janes et al, 2016). A3 receptor activation also attenuates neuroinflammatory responses, astrocyte reactivity, and cytokine release (Janes et al, , 2016.…”

“…In addition, the A3 receptor agonist MRS5698 attenuates KCC2 downregulation and restores Cl 2 gradients in rodent CCI models , a process that may involve attenuation of BDNF signaling (Janes et al, 2016). A3 receptor activation also attenuates neuroinflammatory responses, astrocyte reactivity, and cytokine release (Janes et al, , 2016. Efficacy of A3 receptor agonists such as IB-MECA and MRS5698 in relief of allodynia in rodent models of neuropathic pain has been convincingly demonstrated Little et al, 2015).…”

“…Efficacy of A3 receptor agonists such as IB-MECA and MRS5698 in relief of allodynia in rodent models of neuropathic pain has been convincingly demonstrated Little et al, 2015). Because cardiovascular actions of adenosine are mediated via A1 and A2 adrenoceptors (Sawynok, 2016), A3 agonists show considerable promise as therapeutic agents (Janes et al, 2016). The results of clinical trials are thus eagerly awaited.…”

Polypharmacology of conformationally locked methanocarba nucleosides

“…Purinergic signaling through these receptors, transporters and enzymes has a role in most physiological processes and constitutes a major system for homeostatic control in the body. This has led to numerous therapeutic concepts, such as selective A 3 AR activation for cancer, inflammatory disease, chronic neuropathic pain and other conditions [25,26]. …”