| dc.description | There is increasing evidence indicating that adenosine systems have the potential to be developed as a novel approach to the treatment of neuropathic and inflammatory pain. The present study investigated the involvement of the peripheral adenosine system in a neuropathic pain model and an inflammatory pain model using behavioral and microdialysis approaches. In behavioral studies, tight ligation of the rat spinal nerves L5/L6 induced thermal hyperalgesia and mechanical allodynia. Intraplantar injection of adenosine A1 receptor agonists, an adenosine kinase inhibitor, 5' -amino-5'-deoxyadenosine (NH2dAD) and an adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), into the nerve injured paw, but not the contralateral paw, reversed the thermal hyperalgesia, indicating a local, peripheral effect. The non-selective adenosine receptor antagonist, caffeine, inhibited antihyperalgesic effects, indicating an adenosine receptor mediated mechanism. A1 receptor agonists, but not inhibitors of adenosine metabolism, produced overt paw edema involving mast cells and sensory afferents. Microdialysis studies were conducted in anaesthetized rats to determine subcutaneous adenosine levels in the rat hind paw and the mechanisms mediating the peripheral adenosine release in an inflammatory pain and a neuropathic pain model. Intraplantar injection of formalin, glutamate and capsaicin induced an increase in extracellular adenosine levels. Lower concentrations (0.5--2.5%) of formalin evoked a rapid-onset, short lasting release of adenosine, while at a high concentration (5%), the adenosine release lasted 60min with a much higher magnitude. Intraplantar injection of glutamate (0.03--100mumol) evoked a rapid adenosine release, which can be blocked by N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists. In the neuropathic pain model, saline injection evoked a significant rapid-onset short lasting adenosine release in the ipsilateral paw in the nerve injured rats, but did not induce a release of adenosine in naive rats or sham operated rats. Destroying nociceptive primary sensory afferents with systemic capsaicin pretreatment significantly inhibited adenosine release evoked by 1.5% formalin, the early 20min release evoked by 5% formalin, the glutamate-evoked adenosine release and the saline evoked adenosine release following nerve injury. Destroying sympathetic postganglionic nerves with 6-hydroxydopamine significantly inhibited the later phase of adenosine release evoked by 5% formalin, but did not have an effect in other circumstances. Thus, noxious chemical stimuli such as formalin and glutamate, as well as nerve injury, evoked adenosine release through a nociceptive sensory afferent dependent mechanism. The sympathetic nervous system only contributed to peripheral adenosine release in the circumstances where more pronounced inflammation and tissue damage occurred. Modulation of peripheral extracellular adenosine levels by inhibitors of adenosine metabolism was also studied. In the formalin model, NH2dAD increased adenosine release by 0.5--1.5% formalin and DCF increased the release by 5% formalin. In the neuropathic pain model, both agents did not augment saline-evoked adenosine release. Amitriptyline, an antidepressant producing a peripheral antinociceptive effect through adenosine mechanisms, increased 1.5% formalin and nerve injury-induced adenosine release. In conclusion, noxious chemical stimuli and nerve injury evoke peripheral adenosine release, which can be modulated by inhibitors of adenosine metabolism and other agents to produce a peripheral antinociceptive effect. | en_US |
