HINDBRAIN STRUCTURES INVOLVED IN PAIN PROCESSING AS REVEALED BY THE EXPRESSION OF C-FOS AND OTHER IMMEDIATE-EARLY GENE PROTEINS

We have used the evoked expression of the immediate early gene-encoded proteins (c-Fos, Fos B, Jun B, Jun D, c-Jun and Krox-24) to monitor sensory processing in the hindbrain structures of rats undergoing somatic inflammation. Experiments were performed on freely moving animals that did not experience constraints other than those imposed by the disease itself Local injections of chemicals were used to cause subcutaneous inflammation of the plantar foot or monoarthritis by intracapsular injection. Labelling was studied at survival times that corresponded either to the time points of maximum labelling in the spinal cord (4 h for the subcutaneous model, 24 h and two weeks for the monoarthritis model) or at survival times that corresponded to the chronic phase of monoarthritis evolution (six, nine and 15 weeks). Controls consisted of freely moving, unstimulated animals. Basal expression was observed for all immediate early genes and in a variety of stuctures, but always remained moderate. All immediate early gene-encoded protein expressions except c-dun were evoked, but except for c-Fos, and to a lesser extent Jun D, intensities of staining always remained faint. The following results will be mainly based on c-Fos expression, as this protein proved to be the most effective marker for all the survival times studied. Somatic pain evoked c-Fos expression in a subset of discrete subregions of both the caudal medulla oblongata and transitional areas of the pontomesencephalic junction. In the caudal medulla oblongata, structures involved were the caudal intermediate reticular nucleus, the subnucleus reticularis dorsalis, the ventrolateral reticular formation and the lateral paragigantocellular nucleus. Structures involved at the pontomesencephalic junction level mostly included the superior and dorsal lateral subnuclei of the parabrachial area, the nucleus cuneiformis and the most caudal portions of the lateral central gray, also including the laterodorsal tegmental nucleus; labelling in other lateral subnuclei of the parabrachial area always remained moderate. Staining in the caudal reticular areas was evident only at short survival times (4 and 24 h survival times in subcutaneous and monoarthritis models, respectively). Staining in nuclei of the pontomesencephalic junction was evident in ail cases except for the very long survival periods (six to 15 weeks) of monoarthritis. In all cases staining was bilateral with contralateral predominance with regard to the stimulated limb. The present work demonstrates that hindbrain stuctures involved in somatic pain processing can be effectively identified in behaving animals and that c-Fos is the most reliable activity marker in this case. The structures involved only partially overlap with those implicated in anaesthesia or visceronociceptive processing as demonstrated previously, thus suggesting that a certain degree of specificity could exist for some of them. Nuclei of the caudal medulla oblongata would be more involved in eliciting cardiovascular behaviours that acute pain elicits while nuclei of the pontomesencephalic junction would be more involved in mediating pain of inflammatory origin.