ReviewAdenosine receptor activation and nociception
Introduction
While the ability of adenosine and adenosine 5′-triphosphate (ATP) to alter nociceptive transmission by actions at peripheral and central sites has been recognized for some time (Keele and Armstrong, 1964; Collier et al., 1966; Vapaatalo et al., 1975; Yarbrough and McGuffin-Clineschmidt, 1981), the last decade has seen the development of a particular interest in the role of purines in nociception. A number of reasons account for this focus of attention. (a) Adenosine analogs produce antinociceptive properties in a wide range of test systems, including those for neuropathic pain where pain signalling mechanisms have been altered, and there is an interest in the potential development of adenosine-based pharmaceuticals. (b) Release of adenosine in the spinal cord contributes to the spinal efficacy of opioids, an unusual effect as most actions of opioids are considered inhibitory. (c) Caffeine, an adenosine receptor antagonist, produces adjuvant analgesic properties in combination with non-steroidal anti-inflammatory drugs and acetaminophen; an understanding of the role of adenosine in nociceptive processing is required to understand how caffeine produces such actions. (d) The P2 purinoceptor subtypes involved in nociceptive activation have recently been identified, cloned and shown to have a unique distribution in sensory neurons; this may permit the development of P2 receptor targets for conditions where ATP contributes to the etiology of pain. It is important to appreciate that effects of purines on nociception can be complex, with effects depending on particular receptor subtypes activated and on the localization of the receptor. The following review will summarize the profile of activity of adenosine agents following administration by different routes, consider cellular mechanisms implicated in such actions, and discuss the contribution of interactions with endogenous adenosine systems in the pharmacological actions of other agents. The actions of ATP on nociceptive processing have recently been reviewed elsewhere (Burnstock and Wood, 1996; Sawynok, 1997).
Section snippets
Adenosine A1, A2 and A3 receptors
Multiple chemical mediators contribute to the transduction of pain at peripheral sensory nerve terminals. These include amines (histamine, 5-hydroxytryptamine), kinins (bradykinin), prostanoids (prostaglandins, leukotrienes, hydroxyacids), cytokines (interleukins, tumor necrosis factor), cations (H+, K+), reactive oxygen species, as well as adenosine and ATP (reviewed Levine and Taiwo, 1994; Dray, 1995). The peripheral actions of adenosine in rodents have been characterized primarily using
Antinociceptive properties of adenosine in animals
The first studies to describe antinociceptive activity of adenosine analogs were screening studies in which drugs were administered systemically and a number of behavioural endpoints were assessed (Vapaatalo et al., 1975; Crawley et al., 1981) or when a role of cyclic AMP in the actions of morphine was being addressed (Gourley and Beckner, 1973; Ho et al., 1973). Interest in intrinsic antinociceptive properties of adenosine analogs became much more prominent when the activity of systemically
Caffeine
Caffeine has been combined with aspirin, acetaminophen and other non-steroidal anti-inflammatory agents for some time, but it is only relatively recently that its efficacy in this regard has been convincingly established in humans (Laska et al., 1984; Forbes et al., 1991; Sawynok and Yaksh, 1993). More recent animal based studies have continually demonstrated its adjuvant activity in combination with acetaminophen, aspirin and ketolorac in a newly developed functional impairment model (
Conclusions
Purines can exert complex effects on pain transmission, with prominent actions at both peripheral and spinal sites in preclinical models. The nature of the modulation of pain signalling depends very much upon the receptor subtype activated. In the periphery, adenosine A1 receptor activation produces pain suppression, while adenosine A2 and A3 receptor activation produces pain enhancement. Within the spinal cord, adenosine A1 receptor activation produces antinociception; there are some
Acknowledgements
Work conducted in the authors laboratory was supported by the Medical Research Council of Canada. I thank Allison Reid for her patient reading of the manuscript and references.
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