The Rostral Raphe Pallidus Nucleus Mediates Pyrogenic Transmission from the Preoptic Area

Fever is the widely known hallmark of disease and is induced by the action of the nervous system. It is generally accepted that prostaglandin (PG) E(2) is produced in response to immune signals and then acts on the preoptic area (POA), which triggers the stimulation of the sympathetic system, resulting in the production of fever. Actually, the EP3 subtype of PGE receptor, which is essential for the induction of fever, is known to be localized in POA neurons. However, the neural pathway mediating the pyrogenic transmission from the POA to the sympathetic system remains unknown. To identify the neuronal groups involved in the fever-inducing pathway, we first investigated Fos expression in medullary regions of rats after central administrations of PGE(2). PGE(2) application to the lateral ventricle or directly to the POA strikingly increased the number of Fos-positive neurons in the rostral part of the raphe pallidus nucleus (rRPa). Most of these neurons did not exhibit serotonin immunoreactivity. Microinjection of muscimol, a GABA(A) receptor agonist, into the rRPa blocked fever and thermogenesis in brown adipose tissue induced by intra-POA as well as by intracerebroventricular PGE(2) applications. Furthermore, neural tract tracing studies revealed a direct projection from EP3 receptor-expressing POA neurons to the rRPa. Our results demonstrate that the rRPa, which has never been associated with the fever mechanism, mediates the pyrogenic neurotransmission from the POA to the peripheral sympathetic effectors contributing to fever development.