Central pain after spinal cord injury : experimental studies with special emphasis on pharmacological treatment

Abstract: Injuries and dysfunctions of the central nervous system can cause central pain which, according to clinical experience, is often refractory to conventional treatments. The present thesis consists of experimental studies on the mechanisms and treatments of central pain using a well established animal model of central pain after spinal cord injury. The spinal cord was lesioned by photochemically induced ischemia. During the first week the animals developed various neurological deficits and acute allodynia-like behaviors. With a delay of days to weeks a minority of the injured animals developed a chronic phase of allodynia-like behavior, which resembled the chronic pain syndrome suffered by patients with spinal cord injury. In chronic allodynic animals morphine applied intrathecally (i.t.), but not systemically or intracerebroventricularly, dose dependently alleviated mechanical allodynia without sedation. However, the anti-allodynic potency of morphine was lower than its antinociceptive potency. The data indicate that higher spinal concentration of the opiate is needed for treating central pain after spinal cord injury than nociceptive pain. In acute allodynic animals i.t. morphine did not relieve allodynia, even at high dose. Immunohistochemistry of the g-opioid receptor revealed decreased receptor level shortly after transient spinal cord ischemia, which may contribute to morphine insensitivity. I.t. DAMGO (selective µ-opioid receptor agonist) and DPDPE (selective [delta]-opioid receptor agonist), but not U50488H (selective [kappa]-opioid receptor agonist) dose-dependently alleviated chronic allodynia, suggesting the potential therapeutic value of µ- and [delta]-opioid agonists for treating central pain. However, although i.t. morphine administered twice daily reversed allodynia for 2 days, significant tolerance and dependence developed thereafter. Thus, these well known problems associated with opiate drugs are present even in chronic pain states. I.t., but not intraperitoneal, clonidine dose-dependently relieved the chronic pain-like symptoms and produced no motor deficit or sedation. Since morphine and clonidine synergistically produce analgesia and delay tolerance development, the effect of bovine chromaffin cells, which release enkephalin and catecholamines, was tested. I.t. free bovine chromaffin cells produced an anti-allodynic effect between 1 and 8 weeks after transplantation, with attenuated effect during the last 3 weeks. After 4 weeks no cells with tyrosine hydroxylase (TH) positive immunoreactivity could be found. As a further step, encapsulated bovine chromaffin cells were transplanted to the chronic allodynic animals, which totally alleviated allodynia for the 8 week experimental period. At the termination of the experiment 60-80% of the cells were still TH immunoreactive, indicating functional secreting capacity. Free or encapsulated chromaffin cells may thus provide a novel treatment for this type of pain condition. A subpopulation of spinal cord injured rats did not develop chronic allodynia. In these spinally injured, non-allodynic animals, i.t. naloxone, CTOP (selective µ-opioid receptor antagonist), naltrindole (selective [delta]-opioid receptor antagonist), nor-BNI (selective [kappa]-opioid receptor antagonist), induced mechanical and cold allodynia-like responses dose-dependently, which was not found in normal animals. The tail flick response was not affected by these substances in spinally injured or normal rats. These results provide evidence that the endogenous opioid system is involved in the tonic control of central pain after spinal cord injury. Finally, subcutaneous resiniferatoxin, an ultrapotent capsaicin analogue, markedly increased tail-flick latency of the normal and allodynic rats and also normalized the response to cold, but not mechanical hypersensitivity, of chronic allodynic rats. The data indicate that capsaicin sensitive afferents mediate cold, but not mechanical, allodynia.