adenosine-3--5--cyclic-phosphorothioate and Fever

The present study aimed to test the hypothesis that a decrease in preoptic cAMP mediates fever. To this end, body core temperature (T(c)) of unanesthetized, freely moving rats was monitored by biotelemetry before and after pharmacological modulation of the cAMP pathway, and cAMP levels in the anteroventral third ventricular region (AV3V), where the preoptic region (POA) is located, were determined. We observed that intra-POA administration of the cAMP agonist dibutyryl-cAMP (Db-cAMP, 40 microg) reduced T(c). PGE(2) (the proximal mediator of fever, 200 ng) raised T(c) with a concomitant decrease in AV3V cAMP levels from 22.7+/-1.8 to 17.0+/-1.0 fmol/microg protein. Moreover, PGE(2)-induced fever was impaired by the phosphodiesterase inhibitor aminophylline. In order to verify the interaction between the cAMP- and cGMP-dependent pathways in the POA, we then co-injected Db-cAMP and 8-Br-cGMP into the POA. As a result, 8-Br-cGMP augmented the drop in T(c) evoked by Db-cAMP. Lastly, we observed that intra-POA co-microinjection of the protein kinase A inhibitor (Rp-cAMPS, 1 microg) with the protein kinase G inhibitor (Rp-cGMPS, 1 microg), mimicking the effects of reduced production of cAMP and cGMP, respectively, produced a fever-like response. In summary, the present data support that a decrease in the levels of cAMP and cGMP in the POA is associated with the genesis of fever.

Topics: Aminophylline; Animals; Body Temperature Regulation; Bucladesine; Cyclic AMP; Cyclic GMP; Dinoprostone; Drug Interactions; Fever; Injections, Intraventricular; Lipopolysaccharides; Male; Microinjections; Neurons; Preoptic Area; Rats; Rats, Wistar; Second Messenger Systems; Thionucleotides

To determine whether the cyclic adenosine monophosphate (cAMP) mediated protein kinase signal transduction pathway is involved in the pyrogenic action of corticotropin releasing hormone (CRH) in rats.. Corticotropin releasing hormone, 2',3'-dideoxyadenosine (DDA) and adenosine-3',5'-(cyclic) monophosphorothionate, Rp-Isomer (Rp-cAMPS), were administered intracerebroventricularly (i.c.v.). The colonic temperature was measured using a thermistor, and the content of cAMP in the hypothalamus was determined by radioimmunoassay. Hypothalamic incubation was used to assess the effects of CRH on the content of cAMP in the hypothalamus in vitro.. Microinjection (i.c.v.) of CRH (2.5 micrograms, 5.0 micrograms and 10 micrograms) caused increases in colonic temperature and the hypothalamus cAMP level in conscious rats. CRH increased hypothalamus cAMP level in vitro. The pyrogenic effects of CRH were abolished or markedly inhibited by prior injection (i.c.v.) of an adenylate cyclase inhibitor, DDA (30 micrograms), or an inhibitor of cAMP-dependent protein kinase, Rp-cAMPS (15 micrograms).. cAMP mediates the pyrogenic action of centrally administered of CRH in rats, and protein kinase A may play an important role in the central CRH-induced fever. The cAMP-dependent protein kinase signal transduction pathway may be involved in the central mechanisms of the pyrogenic action of CRH in rats.

Topics: Animals; Body Temperature; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dideoxyadenosine; Fever; Hypothalamus; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Thionucleotides