The dopaminergic network of the periaqueductal grey (PAG) was described several years ago (Lindvall & Björklund, 1974). The periaqueductal grey is a critical locus controlling nociceptive responses, as well as opiate-induced analgesia. However, the role of dopaminergic PAG neurons on nociceptive responses is not known. The objectives of the study were 2-fold: (i) to discern if the dopamine neurons of the PAG are activated after opiate administration, and (ii) to establish the effects of selective lesions of the DA neurons of the PAG on opiate-induced analgesia in rats. Nociceptive threshold was evaluated through the tail-immersion (for evaluating a spinal reflex) and the hot-plate tests (which allows evaluation of more integrated pain-related responses), establishing a short cut-off time (25 s) to further minimize animal suffering. At the end of the experiments the animals were humanely killed. The findings revealed that the dopaminergic cells of the PAG were activated following opiate treatment, since they expressed c-Fos after heroin (500 and 1000 µg kg^-1 S.C.) and morphine (400 and 800 µg kg^-1 S.C.), as evaluated through immunohistochemistry (in comparison with saline-treated rats). Following dopamine depletion of the mesencephalic periaqueductal grey (52.7 % dopamine cell loss, 80.7 % reduction of in vitro dopaminergic peak as measured by voltammetry), the dose-response curve to opiates was shifted to the right in the hot plate test, and analgesia was significantly attenuated (P < 0.01, 2-way ANOVA and post hoc Newman-Keuls test). The present study provides evidence that the dopaminergic network of the periaqueductal grey is activated after opiate treatment, and mediates integrative nociceptive responses since dopamine loss attenuates opiate-induced analgesia in the hot plate test.

This study was supported by Spanish Ministerio de Educacion y Cultura (PM98-015), Plan Andaluz de Investigacion (CVI-127) and Laboratorios Dr Esteve (Barcelona, Spain).