Antinociceptive Effects of Novel A_2B Adenosine Receptor Antagonists

Abstract

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).

Modulation of paracetamol antinociception by caffeine and by selective adenosine A2 receptor antagonists in mice

“…Caffeine (10 mg/kg) administered alone in the tail immersion test produced a pronociceptive effect and abolished the antinociceptive effect of paracetamol. In the hot-plate test caffeine alone also did not produce an antinociceptive effect, in contrast to the results reported by Abo Salem et al (2004). When administered in combination with paracetamol, caffeine again inhibited the effects of paracetamol.…”

“…Abo-Salem et al (2004) reported that PSB1115 at 10 mg/kg did not produce significant antinociception by itself in the hot plate test, but significantly …”

“…Mice weighing 25-30 g received paracetamol, caffeine, the A 2B antagonist PSB1115 (Fredholm et al, 1998;Abo-Salem et al, 2004) or the A 2A antagonist SCH58261 (Zocchi et al, 1996;Fredholm et al, 1998;Abo-Salem et al, 2004) alone or in combination. All drugs were injected intraperitoneally (i.p.)…”

“…The analgesic adjuvant effects of caffeine cannot be due to A 1 receptor blockade, as stimulation of A 1 4 receptors is known to be antinociceptive (Sawynok and Liu, 2003), genetically modified mice lacking the A 1 receptor are hyperalgesic (Johansson et al, 2001;Wu et al, 2005) and A 1 antagonists are pronociceptive (Bastia et al, 2002) or ineffective in animal models of pain (Abo-Salem et al, 2004). Abo-Salem et al (2004) demonstrated that novel selective A 2B adenosine receptor antagonists produced a similar antinociception to caffeine in the hot plate test in mice, raising the possibility that part of the action of caffeine might be mediated at the A 2B receptor. Although they also reported that adenosine A 2A antagonists were not antinociceptive (AboSalem et al, 2004), others have shown antinociceptive effects of A 2A antagonists in the writhing test (Bastia et al, 2002).…”

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

“…A 2 receptor agonists are also pronociceptive in a mechanical paw pressure test in the rat (Taiwo and Levine, 1990), though these early studies used very poorly selective drugs. Added to this, the recent development of highly selective A 2B antagonists shows that these compounds have antinociceptive activity in the hot-plate test (Abo-Salem et al, 2004) and thus the A 2A -A 2B selectivity of the pharmacological tools used in nociceptive studies also needs to be considered alongside their A 1 activity. The literature on A 2A receptor agonists is therefore contradictory although microdialysis studies of the release of adenosine in the hind paw in response to formalin has led to the proposal that adenosine may act at pronociceptive A 2A receptors.…”