Experimental and Clinical Studies on Adenosine Receptor Stimulation in Cutaneous Hypersensitivity and Neuropathic Pain
Sammanfattning: The endogenous compound adenosine (ADO) has a wide range of physiological effects. Numerous animal studies and a limited number of human studies have shown antinociceptive effects of ADO and its analogues. The spinal cord dorsal column, where ADO receptors are found in high numbers, is a major site of action for this effect. While most studies concern acute nociceptive pain, a modulatory effect on neuronal transmission associated with neuropathic pain has been demonstrated in some animal and human studies. The aim of this thesis is to further evaluate effects of ADO receptor stimulation in pain associated with cutaneous hypersensitivity and neuropathia. The ADO analogue R-PIA was administered to rats previously afflicted an incomplete sciatic nerve injury (CCI). "Scratching behaviour" (assumed to reflect spontaneous pain) was reduced following both systemically and intrathecally administered R-PIA, suggesting reduced spontaneous pain in this animal model of neuropathic pain. In a subsequent animal study, the neuropeptide substance P (SP) was reduced in cerebrospinal fluid after intrathecal administration of ADO analogues (R-PIA and NECA). This indicates interactions between ADO receptor mediated mechanisms and SP, a mediator of spinal cord hyperexcitability. In an animal model of central pain, presumed allodynia (pain due to stimulus which does not normally provoke pain) was reduced by intrathecal R-PIA. The duration of this effect was more prolonged than antinociceptive effects of ADO analogues in acute models, suggesting specific effects of ADO receptor stimulation on pathological neuronal transmission associated with neuropathic pain. The effect of systemic ADO infusion on the development of cutaneous hyperalgesia after skin injury (topical mustard oil or heat) was evaluated in healthy human volunteers. The area of secondary hyperalgesia was consistently reduced by ADO. No other effects on sensory function were seen. This indicates ADO induced selective effects on the increased excitability of spinal cord neurons associated with hyperalgesia in uninjured skin. The effects of systemic ADO infusion on tactile dysfunction were assessed in patients with peripheral neuropathic pain. ADO reduced the area of tactile allodynia and induced transient improvements of the clinical pain conditions. This illustrates ADO receptor mediated modulation of the pathophysiological mechanisms involved in spontaneous and evoked neuropathic pain. In conclusion: The studies suggest that ADO mediated mechanisms exert major influences on pain transmission in the hyperexcited nervous system of potential clinical value.
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