Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia

In this study, we examined the effects of systemic and local administration of the subtype-selective adenosine receptor antagonists PSB-36, PSB-1115, MSX-3, and PSB-10 on inflammation and inflammatory hyperalgesia. Pharmacological blockade of adenosine receptor subtypes after systemic application of antagonists generally led to a decreased edema formation after formalin injection and, with the exception of A₃ receptor antagonism, also after the carrageenan injection. The selective A_2B receptor antagonist PSB-1115 showed a biphasic, dose-dependent effect in the carrageenan test, increasing edema formation at lower doses and reducing it at a high dose. A₁ and A_2B antagonists diminished pain-related behaviors in the first phase of the formalin test, while the second, inflammatory phase was attenuated by A_2B and A₃ antagonists. The A_2B antagonist was particularly potent in reducing inflammatory pain dose-dependently reaching the maximum effect at a low dose of 3 mg/kg. Inflammatory hyperalgesia was totally eliminated by the A_2A antagonist MSX-3 at a dose of 10 mg/kg. In contrast to the A₁ antagonist, the selective antagonists of A_2A, A_2B, and A₃ receptors were also active upon local administration. Our results demonstrate that the blockade of adenosine receptor subtypes can decrease the magnitude of inflammatory responses. Selective A_2A antagonists may be useful for the treatment of inflammatory hyperalgesia, while A_2B antagonists have potential as analgesic drugs for the treatment of inflammatory pain.