Treatment of pain behavior after spinal cord injury in rats with special emphasis on the role of adenosine receptors

Sammanfattning: Central pain is a form of neuropathic pain occurring after injury or dysfunction in the central nervous system, including the spinal cord. Allodynia (pain to innocuous stimuli) to mechanical and cold stimulation is a common feature of central pain and it is often resistant to treatment. The present thesis consists of experimental studies on the mechanisms and treatments of presumed central pain in spinally injured rats with emphasis on the role of adenosine, an endogenous inhibitory neuromodulator. The spinal cord injury (SCI) was produced by a photochemically-induced ischemia, where the rats exhibited neurological deficits and acute allodynia-like behavior to mechanical and cold stimulation for a week. With a delay of days to weeks, a sub-population of the injured animals developed a chronic phase of allodynia-like behavior, which in some aspects resembled the central pain suffered by patients after SCI. In rats with chronic allodynia-like behavior, intrathecal (i.t.) R-phenylisopropyl-adenosine (R-PIA), a selective agonist of the adenosine A I receptor, dose-dependently alleviated "allodynia", an effect that was reversed by intraperitoneal theofylline, an antagonist of the adenosine receptors. The anti-allodynic effect of R-PIA was prolonged and was not associated with sedation or motor impairments. In comparison with i.t. morphine, R-PIA was more effective against mechanical than cold allodynia. The anti-allodynic effect of i.t. R-PIA at 10 nmol was maintained for 6-7 days upon twice daily chronic injections, but was reduced thereafter, particularly with respect to cold allodynia. The effect of R-PIA was thus maintained for a longer period than morphine under similar treatment regime. Moreover, there was no exacerbation of allodynia, after development of tolerance to R- PIA. I.t. morphine alleviated allodynia-like behaviors in rats rendered tolerant to R-PIA, similarly as in R-PIA naive rats. Co-administration of R-PIA and morphine produced marked suppression of mechanical allodynia at doses producing no effect on their own. The combination of R-PIA and morphine did not increase adverse effects in comparison to either drug alone. These results indicate that activation of spinal adenosine Al receptors produce anti-allodynic effects in this model of chronic central pain. I.t. R-PIA may have some advantages over morphine when administered chronically. The lack of cross-tolerance between morphine and R-PIA, and a possible synergistic interaction between the two drugs, suggests that the anti-allodynic effect of morphine was not directly mediated by the release of adenosine. In contrast to i.t. R-PIA, the natural ligand adenosine did not reduce allodynia-like behaviors. Instead, an increase in allodynia was observed after i.t. adenosine or mannitol vehicle used in commercially available formulation. The lack of effect of adenosine may be due to pharmacokinetic or pharmacodynamic factors. Alternatively, adenosine may have lower affinity and selectivity towards the adenosine Al receptor than R-PIA. In the last study of the thesis the effects of i.t. R-PIA, morphine, the [alpha]2-adrenoceptor agonist clonidine and the [gamma]-aminobuturic acid (GABA)-B receptor agonist baclofen were compared in treating acute allodynia-like behavior 1-2 days after SCI. Morphine and baclofen were superior to clonidine and R-PIA. Notably, the effect of R-PIA was weaker in alleviating acute than chronic allodynia, indicating that the mechanisms of action of adenosine Al receptor agonists may be dependent on structural and/or functional plasticity in the spinal cord produced by the SCI. In general, the results from these studies support the notion that spinally administered adenosine Al agonists produce analgesia in models of neuropathic pain.