The role of adenosine and its receptor subtypes in nociception and neuropathic pain

As neurotransmitter/modulator, adenosine plays an important role in nociceptive processing. Adenosine receptors are G-protein coupled and four receptor subtypes, A1, A2A, A2B and A3 have been identified. It is well established that adenosine and its receptor agonists produce primarily antinociceptive effect in animals and humans. The physiological significance of endogenous adenosine and its receptors in pain modulation, including neuropathic pain (pain after injury or diseases to the nervous system) is, however, less clear. In the first part of this thesis, we have used mice with targeted deletion of adenosine A1 and A3 receptors to explore their individual roles in nociception. In the second part of the thesis, we studied the effect of caffeine, a non-selective antagonist of adenosine receptors, in a rat model of neuropathic pain and explored potential genetic factors in the antinociceptive effect of the adenosine analogue R (-N 6 -2-Phenylisopropyl) adenosine (R-PIA) using inbred mice. To aid these studies, we developed anew method for chronic intrathecal (i.t.) catheterization in mice. A1, but not A3, knock out mice exhibited heat hyperalgesia under normal condition and after carrageenan-induced inflammation, suggesting that the A1 receptor is physiologically active in inhibiting nociceptive input. A1 receptor, on the other hand, does not seem to play a role in localized inflammatory reaction to carrageenan. In contrast, canageenan-induced inflammation was reduced in the periphery in the A3 knock-out mice, which was associated with reduced inflammatory hyperalgesia. This suggests that adenosine A3 receptors play a pro-inflammatory role in peripheral tissues. The antinociceptive effect of i.t. R-PIA was abolished in A1, but not A3, knock-out mice. Further, the antinociceptive effect of i.t., but not systemic, morphine was also reduced in A, knockout mice. These results suggest that the spinal A1 receptor is critical for adenosine analogue-mediated antinociception