Evidence that cyclic nucleotides are not mediators of fever in rabbits

Dascombe, Michael J.

doi:10.1111/j.1476-5381.1984.tb16122.x

Cited by 13 publications

(11 citation statements)

References 23 publications

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“…Although we have previously observed a biphasic hypo-/hyperthermic response to intra-POA microinjected (rather than microdialyzed) clonidine (55), in that study in contrast to the present one, the ␣ 2 -AR antagonist rauwolscine microinjected 10 min before clonidine abolished the hypothermia without affecting the subsequent hyperthermia; the latter was attenuated by the intramuscular injection of the nonspecific COX inhibitor indomethacin 20 min after the intra-POA microinjection of clonidine. This response was similar to that to dibutyryl-cAMP reported by Dascombe (11,12). We interpreted those data as verifying the ␣ 2 -AR-mediated hypothermic action of clonidine and, like Dascombe, attributed the subsequent T c rise to contamination of the thermal response to this agonist by PGE 2 released in the POA consequent to the acute inflammatory response to the microinjection procedure per se (57).…”

Section: Discussionsupporting

confidence: 71%

“…Thus 1) various lines of evidence have indicated that NE induces the production of cAMP in firstorder neurons in hypothalamic tissue slices (17); it is controversial, however, whether it does so by stimulating ␣ 1 -or ␣ 2 -ARs (52, 59). It was also reported long ago (11,12) that the intra-POA microinjection of its analog agonist, dibutyrylcAMP, into rabbits and rats causes a rapid fall followed by a prolonged rise in T c and that the latter rise is blocked by acetaminophen, then a nonspecific COX inhibitor, but lately a putatively specific inhibitor of the presumptive COX-1 variant, COX-3 (61). This late rise was attributed to PGE 2 generated in consequence of tissue damage associated with the microinjection procedure per se.…”

Section: Discussionmentioning

confidence: 99%

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

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In 1984, Dascombe (13) reported that intra-POA administration of a cGMP analog reduces the T c of rabbits. Considering that NO produces many of its effects through a cGMP-dependent pathway (38,48), one would expect NO to be an antipyretic molecule in the POA.…”

mentioning

confidence: 99%

Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain

Steiner

Antunes‐Rodrigues

McCann

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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We tested the hypothesis that nitric oxide (NO) acts in the anteroventral preoptic region (AVPO) modulating fever. To this end, body core temperature (T(c)) of rats was monitored by biotelemetry before and after pharmacological modulation of the NO pathway. Nitrite/nitrate and cGMP in the anteroventral third ventricular region (AV3V), where the AVPO is located, were also determined. Intra-AVPO microinjection of the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 12.5 microg) did not affect basal T(c), but it enhanced the early stage of lipopolysaccharide (LPS) fever, indicating that NO plays an antipyretic role in the AVPO. In agreement, intra-AVPO microinjection of the NO donor sodium nitroprusside (5 microg) reduced T(c). The antipyretic effect of NO seems to be mediated by cGMP because 1) NO has been shown to activate soluble guanylate cyclase, 2) intra-AVPO microinjection of 8-bromo-cGMP (8-BrcGMP) reduced T(c), and 3) the changes in AV3V levels of nitrite/nitrate and cGMP were similar in the course of fever. Additionally, we observed that nitrite/nitrate and cGMP levels decreased in the AV3V after, but not before, the onset of LPS fever, showing that the activity of the NO-cGMP pathway is reduced in the AV3V after intraperitoneal LPS, a mechanism that could contribute to the genesis and maintenance of fever. It was also observed that the efficacy of 8-BrcGMP in reducing T(c) in the AVPO is increased after LPS, emphasizing that the NO-cGMP pathway is antipyretic. This response could explain why intra-AVPO L-NMMA enhanced the early stage of LPS fever, even though the activity of the NO pathway before the onset of fever was unchanged. In summary, these data support an antipyretic role of the NO-cGMP pathway in the AVPO.

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“…The rostral hypothalamus, especially the POAH, is an important neural region controlling body temperature by heat loss, heat retention, and heat production responses (1). Whole animal studies suggest that cGMP plays a role in the neural control of these responses since changes in hypothalamic cGMP consistently produce changes in body temperature (6,7,20,21,34). When hypothalamic cGMP levels increase, body temperature decreases, and when hypothalamic cGMP levels decrease (via inhibition of sGC), body temperature increases.…”

Section: Discussionmentioning

confidence: 98%

“…When cGMP analogs are microinjected in the POAH or administered intracerebroventricularly (icv), there are consistent decreases in body temperature in rats (34), guinea pigs (21), rabbits (6,20), and cats (7). These previous studies used either dibutyryl cGMP or 8-bromo-cGMP (8-Br-cGMP), i.e., analogs that are more membrane permeable and more resistant to phosphodiesterase degradation compared with native cGMP.…”

mentioning

confidence: 95%

Cyclic GMP alters the firing rate and thermosensitivity of hypothalamic neurons

Wright

Burgoon²,

Bishop³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Wright CL, Burgoon PW, Bishop GA, Boulant JA. Cyclic GMP alters the firing rate and thermosensitivity of hypothalamic neurons. The rostral hypothalamus, especially the preoptic-anterior hypothalamus (POAH), contains temperature-sensitive and -insensitive neurons that form synaptic networks to control thermoregulatory responses. Previous studies suggest that the cyclic nucleotide cGMP is an important mediator in this neuronal network, since hypothalamic microinjections of cGMP analogs produce hypothermia in several species. In the present study, immunohistochemisty showed that rostral hypothalamic neurons contain cGMP, guanylate cyclase (necessary for cGMP synthesis), and CNG A2 (an important cyclic nucleotide-gated channel). Extracellular electrophysiological activity was recorded from different types of neurons in rat hypothalamic tissue slices. Each recorded neuron was classified according to its thermosensitivity as well as its firing rate response to 2-100 M 8-bromo-cGMP (a membrane-permeable cGMP analog). cGMP has specific effects on different neurons in the rostral hypothalamus. In the POAH, the cGMP analog decreased the spontaneous firing rate in 45% of temperature-sensitive and -insensitive neurons, an effect that is likely due to cGMP-enhanced hyperpolarizing K ϩ currents. This decreased POAH activity could attenuate thermoregulatory responses and produce hypothermia during exposures to cool or neutral ambient temperatures. Although 8-bromo-cGMP did not affect the thermosensitivity of most POAH neurons, it did increase the warm sensitivity of neurons in other hypothalamic regions located dorsal, lateral, and posterior to the POAH. This increased thermosensitivity may be due to pacemaker currents that are facilitated by cyclic nucleotides. If some of these non-POAH thermosensitive neurons promote heat loss or inhibit heat production, then their increased thermosensitivity could contribute to cGMP-induced decreases in body temperature. guanosine monophosphate; neuronal activity; soluble guanylate cyclase; cyclic nucleotide-gated channel; immunohistochemistry; electrophysiology NEURONS IN THE ROSTRAL HYPOTHALAMUS, especially in the preoptic-anterior hypothalamus (POAH), are important in the regulation of body temperature. Thermosensitive POAH neurons sense changes in the central core temperature, and these same neurons receive synaptic afferent inputs from skin thermoreceptors (1, 2). This integration of central and peripheral thermal information produces appropriate physiological and behavioral responses that regulate body temperature. Both in vivo and in vitro electrophysiological studies have recorded the activity of POAH neurons during changes in hypothalamic temperature (17,19,24,27). Although the majority of these neurons are considered to be temperature insensitive, at least 20% are classified as warm sensitive because their firing rates significantly increase during hypothalamic warming and decrease during hypothalamic cooling. Thermosensitivity is an intrinsic property of these warm-sensitive neuro...

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Evidence that cyclic nucleotides are not mediators of fever in rabbits

Cited by 13 publications

References 23 publications

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

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

Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain

Cyclic GMP alters the firing rate and thermosensitivity of hypothalamic neurons

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Evidence that cyclic nucleotides are not mediators of fever in rabbits

Cited by 13 publications

References 23 publications

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

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

Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain

Cyclic GMP alters the firing rate and thermosensitivity of hypothalamic neurons

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Resources

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

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