Controlling murine and rat chronic pain through A ₃ adenosine receptor activation

Abstract

Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A(3) adenosine receptor (A(3)AR) agonism as a new target-based therapeutic strategy. The development of mechanoallodynia in a well-characterized mouse model of neuropathic pain following chronic constriction injury of the sciatic nerve was rapidly and dose-dependently reversed by the A(3)AR agonists: IB-MECA, its 2-chlorinated analog (Cl-IB-MECA), and the structurally distinct MRS1898. These effects were naloxone insensitive and thus are not opioid receptor mediated. IB-MECA was ≥1.6-fold more efficacious than morphine and >5-fold more potent. In addition, IB-MECA was equally efficacious as gabapentin (Neurontin) or amitriptyline, but respectively >350- and >75-fold more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB-MECA significantly increased the antiallodynic effects of all 3 analgesics. Moreover, neuropathic pain development in rats caused by widely used chemotherapeutics in the taxane (paclitaxel), platinum-complex (oxaliplatin), and proteasome-inhibitor (bortezomib) classes was blocked by IB-MECA without antagonizing their antitumor effect. A(3)AR agonist effects were blocked with A(3)AR antagonist MRS1523, but not with A(1)AR (DPCPX) or A(2A)AR (SCH-442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A(3)AR agonists for 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 protective effects of A 3 AR agonists were naloxoneinsensitive and thus are not opioid receptor mediated [9]. MRS5698 was at least 1.6-fold more efficacious than morphine and over 5-fold more potent [15].…”

“…Three silk sutures (4-0) with about 1-mm spacing were tied around the nerve causing slight constriction. CCI-induced mechano-allodynia peaks at 7 days (D7) post-surgery, which was the time point used for pharmacological experiments (9,14).…”

“…We aim to develop a small molecule that acts as an A 3 adenosine receptor (AR) agonist for the treatment of chronic neuropathic pain, as indicated in animal models [9][10][11]. There is a need to develop new drugs for this widespread condition, especially one acting by a novel mechanism, because current treatment is not very effective or is associated with severe or disturbing side effects.…”

“…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]. The development of chemotherapy-induced neuropathic pain in mice in the CCI model was completely prevented by MRS5698 (1.0 mg/kg, i.p.…”

“…given at the time peak pain is reached, i.e., 7 days). A 3 AR agonists are inactive in models of acute pain, such as tail flick and hot plate assays [9]. Here, we delve further into the drug-like properties of MRS5698, which we prepare on a large scale by a more practical synthetic route from bulk starting materials ( Figs.…”