Chronic activation of spinal adenosine A1 receptors results in hypersensitivity

Spinally administered adenosine reduces hypersensitivity in animals and humans with nerve injury, but also causes transient pain in humans and reduces tonic inhibition in spinal neurons. Nerve injury results in increased tonic spinal cord adenosine A1 receptor activation, consistent with a role for adenosine to generate hypersensitivity. Here, we demonstrate that chronic intrathecal adenosine induces hypersensitivity in normal animals and that chronic blockade of spinal adenosine A1 receptors by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine partially prevents nerve injury-induced hypersensitivity. In contrast, chronic blockade of spinal adenosine A1 receptors failed to reduce increased tonic G-protein signaling in the spinal cord after nerve injury. These data support a role for chronic adenosine A1 receptor stimulation after nerve injury to result in hypersensitivity.