5'-Chloro-5'-deoxy-(±)-ENBA, a Potent and Selective Adenosine A1 Receptor Agonist, Alleviates Neuropathic Pain in Mice Through Functional Glial and Microglial Changes without Affecting Motor or Cardiovascular Functions

Abstract

This study was undertaken in order to investigate the effect of chronic treatment with 5′-chloro-5′-deoxy-(±)-ENBA, a potent and highly selective agonist of human adenosine A1 receptor, on thermal hyperalgesia and mechanical allodynia in a mouse model of neuropathic pain, the Spared Nerve Injury (SNI) of the sciatic nerve. Chronic systemic administration of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p.) reduced both mechanical allodynia and thermal hyperalgesia 3 and 7 days post-SNI, in a way prevented by DPCPX (3 mg/kg, i.p.), a selective A1 adenosine receptor antagonist, without exerting any significant change on the motor coordination or arterial blood pressure. In addition, a single intraperitoneal injection of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p.) 7 days post-SNI also reduced both symptoms for at least two hours. SNI was associated with spinal changes in microglial activation ipsilaterally to the nerve injury. Activated, hypertrophic microglia were significantly reduced by 5′-chloro-5′-deoxy-(±)-ENBA chronic treatment. Our results demonstrated an involvement of adenosine A1 receptor in the amplified nociceptive thresholds and in spinal glial and microglial changes occurred in neuropathic pain, without affecting motor coordination or blood pressure. Our data suggest a possible use of adenosine A1 receptor agonist in neuropathic pain symptoms.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms

“…At 1 mg/kg i.p., Cl-ENBA was largely selective for A 1 AR, although at 3 mg/kg some of the effect was contributed by A 3 AR. Cl-ENBA is anti-nociceptive in the mouse at 0.5 mg/kg (Luongo et al , 2012), suggesting that this effect is via A 1 AR. Cl-ENBA’s greater selectivity makes it a preferred agonist for investigating in vivo A 1 AR physiology, at least in mice.…”

Rational Design of Sulfonated A3 Adenosine Receptor-Selective Nucleosides as Pharmacological Tools To Study Chronic Neuropathic Pain

“…13,14,41,42 The sulfonated agonists are introduced here as a means of separating the peripheral and central effects of AR agonists, depending on the route of administration. Upon i.p.…”

Medicinal chemistry of adenosine, P2Y and P2X receptors

“…A 1 -selective nonnucleoside derivative capadenoson (BAY68-4986) 9 is in trials for treatment of persistent atrial fibrillation and is now available as a research tool (Tendera et al ., 2012). Compound 10 is highly selective for the A 1 AR and displayed analgesic activity in the formalin test in mice (Luongo et al , 2012, Franchetti et al , 2009). Compound 11 is a peripherally-selective agonist, due to its permanently charged sulfonate group, that is moderately A 1 AR selective (70-fold).…”