Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR alpha3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR alpha3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR alpha3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR alpha3 may provide a previously unrecognized molecular target in pain therapy.

Caffeine, an adenosine A 1 , A 2A , and A 2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A 2B -selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A 1 -and A 2A -selective compounds did not alter pain thresholds, and an A 3 adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A 2B -selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A 2B adenosine receptors.Caffeine has intrinsic antinociceptive properties and is frequently used as an adjuvant analgesic drug (Malec and Michalska, 1988;Sawynok and Yaksh, 1993). Although it is thought that caffeine analgesia is produced, at least in part, through adenosine receptor antagonism, it is unclear which receptor subtypes are involved. The adenosine receptor family comprises four subtypes: A 1 , A 2A , A 2B , and A 3 (Fredholm et al., 2001). They are widely distributed in the CNS and peripheral tissues. The A 1 receptors are found in high density in the brain (cortex, cerebellum, and hippocampus) and the dorsal horn of the spinal cord, and at lower levels in other brain regions and in peripheral tissues (Rivkees et al., 1995;Fredholm et al., 2001). The A 2A receptors show a more restricted expression pattern in the CNS with high levels in the striatum, nucleus accumbens, and olfactory tubercle (Ongini and Fredholm, 1996). In the periphery, A 2A receptors are highly expressed in spleen, thymus, leukocytes, and blood platelets (Ongini and Fredholm, 1996). A 2B and A 3 receptors are widely distributed, but have a low density in the CNS (Dixon et al., 1996). In the periphery, A 2B receptors are highly expressed in the large intestine, on mast cells and hematopoietic cells (Feoktistov and Biaggioni, 1995). A 3 receptors show a species-dependent distribution: in rats, testis and mast cells express A 3 receptors in high density (Salvatore et al., 1993), whereas humans exhibit high A 3 receptor expression in the lung and in cells of the immune system (Salvatore et al., 1993).A 1 receptors can couple to G i , thus inhibiting the formation of cAMP, whereas stimulation of A 2 receptors, which bind to G s leads to an increase in adenylate cyclase activity (Fredholm et al., 2001).