Adenosine kinase and adenosine deaminase inhibition modulate spinal adenosine- and opioid agonist-induced antinociception in mice

Keil, Gary J.; DeLander, Gary E.

doi:10.1016/0014-2999(94)90262-3

Cited by 53 publications

(19 citation statements)

References 31 publications

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“…Morphine enhances the release of adenosine from the spinal cord and cortex (Phillis et al, 1980;Cahill et al, 1996), presumably through a synergistic activation of and ␦ opioid receptors (Cahill et al, 1996). Pharmacological studies have indicated that the A 1 and A 2A receptors may be downstream mediators of morphine analgesia (Keil and DeLander, 1994;Sawynok, 1998), although studies in A 2A knockout mice failed to reveal any differences in receptor-dependent analgesia (Bailey et al, 2002). The results from this study indicate that the analgesic effects of centrally released adenosine may be counterbalanced by pronociceptive A 2B receptor-mediated peripheral effects of adenosine.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists

Abo-Salem

Hayallah²,

Bilkei-Gorzó³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

137

111

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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).

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Section: Discussionmentioning

confidence: 99%

Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists

Abo-Salem

Hayallah²,

Bilkei-Gorzó³

et al. 2004

The Journal of Pharmacology and Experimental Therapeutics

137

111

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“…As in epilepsy, adenosine provides potent inhibition to hyperexcitable neuronal circuits resulting in profound antinociceptive effects of adenosine (Lynch et al, 2003;Sawynok and Liu, 2003). Consequently, ADK inhibitors have been considered as a very attractive target for the treatment of various pain states, and proof of feasibility studies with prototypes of ADK inhibitors have demonstrated efficacy in several animal models of nociception (Keil and DeLander, 1994;Sawynok, 1995, 1998;Sawynok and Liu, 2003). Unfortunately, short half lives in vivo, poor bioavailability, lack of pharmacological selectivity, and potential to form cytotoxic metabolites limited further preclinical testing of those prototype inhibitors (Cottam et al, 1993;Wiesner et al, 1999;Ugarkar et al, 2000a).…”

Section: B Applications In Preclinical Studiesmentioning

confidence: 99%

Adenosine Kinase: Exploitation for Therapeutic Gain

Boison

2013

Pharmacological Reviews

263

323

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“…The tail-flick model involves spinal nociceptive reflex, thus being suitable for the study of the adenosinergic influence in spinal cord (29). Rats were wrapped in a towel and placed on the apparatus.…”

Section: Tail-flick Measurementmentioning

confidence: 99%

Nociceptive Response and Adenine Nucleotide Hydrolysis in Synaptosomes Isolated from Spinal Cord of Hypothyroid Rats

et al. 2005

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Purinergic system exerts a significant influence on the modulation of pain pathways at the spinal site. Adenosine has antinociceptive properties in experimental and clinical situations, while ATP exerts pronociceptive actions in different pain models. In this study we investigated the hydrolysis of ATP to adenosine in synaptosomes from spinal cord in parallel with the nociceptive response of rats at different ages after hypothyroidism induction. Hypothyroidism elicited a significant increase in AMP hydrolysis to adenosine in synaptosomes from spinal cord of rats subjected to neonatal hypothyroidism and in 420-day-old rats submitted to thyroidectomy. Accordingly, these rats presented an analgesic response as a consequence of hypothyroidism. In contrast, the ATP hydrolysis was decreased in the spinal cord of 60-day-old hypothyroid rats in parallel with a significant increase in nociceptive response. These results indicate the involvement of adenine nucleotides in the control of the hypothyroidism-induced nociceptive response during development.

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Adenosine kinase and adenosine deaminase inhibition modulate spinal adenosine- and opioid agonist-induced antinociception in mice

Cited by 53 publications

References 31 publications

Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists

Antinociceptive Effects of Novel A2B Adenosine Receptor Antagonists

Adenosine Kinase: Exploitation for Therapeutic Gain

Nociceptive Response and Adenine Nucleotide Hydrolysis in Synaptosomes Isolated from Spinal Cord of Hypothyroid Rats

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