Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states

Abstract

Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.

Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain

“…These studies have identified MRS5698 as a potent and selective A 3 AR agonist with K i =~3 nM for both human and mouse A 3 AR. Moreover, MRS5698 is efficacious in models of chronic and prolonged neuropathic pain in mice and rats [10,15], including bone cancer pain. In order to assess its preclinical properties, we have developed a more practical synthetic route and further evaluated MRS5698 in vivo and in vitro.…”

“…Pain model CCI was performed as previously reported [15,16]. Animals were anesthetized with 3 % isoflurane/100 % O 2 inhalation and maintained on 2 % isoflurane/100 % O 2 .…”

“…in rats and 1.7 mg/kg (p.o.) in mice [15,30], suggesting that MRS5698 has an acceptable therapeutic index.…”

“…The unambiguous pharmacological characterization of chronic pain protection by A 3 AR agonists in vivo at spinal and supraspinal sites is based on the use of selective agonists and antagonists, as well as A 3 AR knock-out mice and the inhibition of adenosine kinase [15]. MRS5698 demonstrated pharmacological activity in multiple mouse and rat models of chronic neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve [9,16] or by the chemotherapeutic agent oxaliplatin [10].…”

Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

“…By comparison, the reference agonist 10 displayed an ED 50 value of 0.55 mg/kg. 4 For comparison with an established treatment of neuropathic pain, the ED 50 of gabapentin (i.p.) at maximal reversal (1 h) in the CCI model was 140 μmol/kg, 18 i.e., much less potent than 10 and 11 (footnote b, Table 1).…”