Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Abstract

Feleder, Carlos, Vit Perlik, and Clark M. Blatteis. Preoptic ␣1-and ␣2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs. Am J Physiol Regul Integr Comp Physiol 286: R1156 -R1166, 2004. First published February 12, 2004 10.1152/ajpregu.00486.2003We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE2 release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE2 and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (␣1-AR agonist), and clonidine (␣2-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (Tc) and intra-POA PGE2 responses. Cirazoline induced Tc rises promptly after the onset of its dialysis without altering PGE2 levels. NE and clonidine caused early falls followed by late rises of Tc; intra-POA PGE2 levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced Tc and PGE2 falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine-and NE-induced Tc and PGE2 rises. Coinfused cirazoline and clonidine reproduced the late Tc rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE2 responses were similar to those to NE. Prazosin (␣1-AR antagonist) and yohimbine (␣2-AR antagonist) blocked the effects of their respective agonists. These results indicate that ␣1-and ␣ 2-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct Tc responses: ␣1-AR activation produces quick, PGE2-independent T c rises, and ␣2-AR stimulation causes an early Tc fall and a late, COX-2/PGE2-dependent Tc rise. thermoregulation; cyclooxygenase inhibitors; prostaglandin E 2; noradrenergic agonists and antagonists; care temperature; norepinephrine THERE IS MUCH EVIDENCE that norepinephrine (NE) and prostaglandin (PG) E 2 interact in many tissues, including nervous tissue (33). For example, an intimate association between NE and PGE 2 is well documented in the peripheral nervous system (21); to wit, the stimulation of sympathetic neurons induces the postsynaptic release of PGE 2 , which then limits the further presynaptic release of NE, thereby modulating the activity of noradrenergic neurons. It is also well documented that NE induces PGE 2 synthesis in brain tissue (23, 60) where its feedback inhibition of the presynaptic release of NE has been similarly documented (3,13,54).In conscious guinea pigs, NE microinjected into the preoptic-anterior hypothalamic area [POA, the locus of the thermal controller (7)] evokes body (core) temperature (T c ) rises (75,47). Electrical stimulation of the ascending noradrenergic system in the brain stem yields the same result (67), whereas chemical sympat...

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

“…Antagonism of the alpha-1 ARs adds support for this observation, ultimately hindering rapid onset of fever and reducing its high point (Feleder, 2004). It has also been established that hepatic vagal afferents are necessary to promptly convey information from the immune system to the hypothalamus and initiate a fever in response to peripheral LPS exposure (Simons et al, 1998;MohanKumar et al, 2000).…”

“…It appears that POAH neurons can be affected by the alpha-1 AR agonist Cirazoline, since its microdialysis in the POAH produces a prompt rise in body temperature. This is in contrast to the delayed temperature rise mediated by the alpha-2 AR receptors that induces and is dependent on PGE 2 production, and is important in the late phase of the febrile response (Feleder et al, 2004).…”

“…As the alpha-1 AR has been implicated in initiating a rapid, PGE 2 -independent early hyperthermia (Feleder et al, 2004), we argued that based on the body of knowledge supporting Hammel's model of thermoregulation (Hammel, 1965), Cirazoline would result in a decrease and increase of firing rates respectively of warm sensitive and temperature insensitive neurons in the POAH. Our findings clearly demonstrate the alpha-1 AR agonist produces these contrasting effects in the two distinct populations of neurons.…”

“…It is clear that norepinephrine has a thermogenic effect in the POAH, resulting in a core temperature rise (Zeisberger, 1987), as well as promoting PGE 2 release (Feleder et al, 2004). Specifically, the microdialysis of norepinephrine in the POAH results in two unique thermal responses which are mediated through the actions of two adrenoreceptors (AR; Feleder et al, 2004).…”

“…Specifically, the microdialysis of norepinephrine in the POAH results in two unique thermal responses which are mediated through the actions of two adrenoreceptors (AR; Feleder et al, 2004). The alpha-1 AR, a G-protein coupled receptor, is present on thermosensitive neurons of the POAH (Mallick et al, 2002), and is thought to increase sodium pump activity (Mallick et al, 2000).…”