Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. I. Effects after oral administration

Background and purpose: Retinoic acid is an active metabolite of vitamin A involved in the modulation of the inflammatory and nociceptive responses. The aim of the present study was to analyze the properties of spinal cord neuronal responses of male Wistar rats treated with all-trans retinoic acid (ATRA) p.o. in the normal situation and under carrageenan-induced inflammation. We also studied the expression and distribution of cyclooxygenases (COX) in the spinal cord. Experimental approach: Properties of spinal cord neurons were studied by means of the single motor unit technique. The expression of COX enzymes in the spinal cord was assessed by Western blot analysis and immunohistochemistry. Key results: Intensity thresholds for mechanical and electrical stimulation (C-fibers) were significantly lower in animals treated with ATRA than vehicle, either in normal rats or in rats with inflammation. The size of cutaneous receptive fields was also larger in animals treated with ATRA in the normal and inflammatory conditions. The expression of COX-2 enzyme, but not COX-1, was significantly higher in animals treated with ATRA. COX-2 labeling was observed in dorsal horn cells and in ventral horn motoneurons. Conclusions and implications: In conclusion, the oral treatment with ATRA in rats induces a sensitization-like effect on spinal cord neuronal responses similar to that observed in animals with inflammation and might explain the enhancement of allodynia and hyperalgesia observed in previously published behavioral experiments. The mechanism of action involves an over-expression of COX-2, but not COX-1, in dorsal and ventral horn areas of the lumbar spinal cord.