Formalin-induced pain and m-opioid receptor density in brain and spinal cord are modulated by A1 and A2a adenosine agonists in mice

The effects of adenosine analogues on pain have been shown to depend on the subtype receptor involved as well as on the nociceptive stimuli and on the route of administration. In the first experiment of the present study the intraperitoneal administration of the A1 receptor agonist N6-cyclopentyladenosine (CPA) (0.015, 0.03, 0.09, 0.15, 0.21, 0.3 mg/Kg) induced dose-dependent analgesia to formalin pain in both phases characterizing the test. The A2a receptor agonist 2-[p-2-carbonyl-ethyl)-phenyethylamino]-5’-N-ethylcarboxaminoadeno sine (CGS21680) (0.025, 0.05, 0.1, 0.15 mg/Kg) significantly affected behavioral responses to formalin only during the early phase. In the second experiment the interaction between adenosine and the opioid system was investigated through both behavioral and neurochemical studies. The opioid antagonist naltrexone (0.1 mg/Kg) did not affect the antinociception induced by CPA (0.21 mg/Kg) and CGS21680 (0.05 mg/Kg). Autoradiographic studies showed that formalin administration significantly modified m opioid receptor density in the superficial laminae of the spinal cord and in the paracentral thalamic nucleus, contralateral to the side of formalin injection. CPA and CGS21680 counteracted these effects induced by formalin. In conclusion the present study confirms and extends the role of A1 and A2a adenosine receptors in the modulation of inflammatory pain and their interaction with the m opioid system, and suggests to further investigate these purinergic receptors also in a therapeutic perspective.