Kae Oka

Mechanisms and mediators of psychological stress-induced rise in core temperature.

Objective Despite numerous case reports on “psychogenic fever,” it remains uncertain how psychological stress raises core temperature and whether the rise in core temperature is a real fever or a hyperthermia. This article reviews studies on the psychological stress–induced rise in core temperature (PSRCT) in animals with the aim to facilitate studies on the mechanisms of so-called psychogenic fever in humans. Methods To address this question, we reviewed the mechanisms and mediators of the PSRCT and classic conditioning of the fever response in animals. Results The PSRCT is not due to the increased locomotor activity during stress, and the magnitude of the PSRCT is the same in warm and cold environments, indicating that it is a centrally regulated rise in temperature due to an elevated thermoregulatory “set point.” The PSRCT caused by conventional psychological stress models, such as open-field stress, is attenuated by cyclooxygenase inhibitors, which block prostaglandin synthesis. On the other hand, the PSRCT elicited by an “anticipatory anxiety stress” is not inhibited by cyclooxygenase inhibitors but by benzodiazepines and serotonin Type 1A receptor agonists. The febrile response can be conditioned to neutral stimuli after paired presentation with unconditioned stimuli such as injection of lipopolysaccharide, a typical pyrogen. Conclusions Most findings indicate that the PSRCT is a fever, a rise in the thermoregulatory set point. The PSRCT may occur through prostaglandin E2–dependent mechanisms and prostaglandin E2–independent, 5-HT–mediated mechanisms. The febrile response can be conditioned. Thus, these mechanisms might be involved in psychogenic fever in humans.

Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats.

We assessed the effect of interleukin-6 (IL-6) in the brain on nociception by using the hot-plate test in rats. Recombinant human IL-6 (rhIL-6, 30 pg-300 ng) was microinjected into the lateral cerebroventricle (LCV) and the paw-withdrawal latency was then measured for 60 min after injection. RhIL-6 at 300 pg reduced the paw-withdrawal latency at 15 min after injection. Further increase of rhIL-6 doses to 3, 30 and 300 ng resulted in the decreased paw-withdrawal latency at 15 and 30 min. Although the peak responses observed at 3-300 ng did not differ significantly, the time taken for recovery tended to be longer with increasing doses. The rhIL-6 (30 ng)-induced reduction of the paw-withdrawal latency was completely blocked by the co-injection of either Na salicylate (30 ng, LCV) or alpha-melanocyte stimulating hormone (30 ng, LCV), an anti-cytokine substance. However, it was not affected by the co-injection of IL-1 receptor antagonist (30 ng, LCV) which had been previously shown to be able to block IL-1 beta-induced hyperalgesia. These findings indicate that IL-6 in the brain induces hyperalgesia by its prostanoids-dependent action in rats. The hyperalgesic action of central IL-6 thus does not appear to depend on the action of IL-1.

The opposing effects of interleukin-1 β microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats

The effects of microinjections of recombinant human interleukin-1 beta (rhIL-1 beta) into the hypothalamus and neighboring basal forebrain on nociceptive behavior were studied using a hot-plate test in rats. The microinjection of rhIL-1 beta at doses between 5 pg/kg and 50 pg/kg into the medial part of the preoptic area (MPO) reduced the paw-withdrawal latency. The maximal reduction was obtained 30 min after the injection of rhIL-1 beta at 20 pg/kg. RhIL-1 beta (20 pg/kg)-induced hyperalgesia was completely blocked by the simultaneous injection of IL-1 receptor antagonist (IL-1ra, 20 ng/kg), Na salicylate (200 ng/kg) or alpha-melanocyte-stimulating hormone alpha-MSH, 20 ng/kg). The intra-MPO injection of rhIL-1 beta at doses of less than 5 pg/kg or more than 50 pg/kg (up to 2 ng/kg) into the paraventricular nucleus, the lateral hypothalamic area and the septal nucleus had no effect on nociception. The microinjection rhIL-1 beta (20 pg/kg-50 pg/kg) into the ventromedial hypothalamus produced a prolongation of the paw-withdrawal latency. A maximal prolongation was obtained 10 min after the injection of rhIL-1 beta at 50 pg/kg. This reaction was also blocked by the simultaneous injection of IL-1ra (50 ng/kg) and Na salicylate (500 ng/kg). These findings indicate that IL-1 beta in the MPO and the VMH produces hyperalgesia and analgesia, respectively, while, in addition, both effects are mediated by IL-1 receptors and the synthesis of prostaglandins.

Hypothalamic Mechanisms of Pain Modulatory Actions of Cytokines and Prostaglandin E2

Abstract: A decrease and subsequent increase in nociceptive threshold in the whole body are clinical symptoms frequently observed during the course of acute systemic infection. These biphasic changes in nociceptive reactivity are brought about by central signal substances induced by peripheral inflammatory messages. Systemic administration of lipopolysaccharide (LPS) or interleukin‐1β (IL‐1β), an experimental model of acute infection, may mimic the biphasic changes in nociception, hyperalgesia at small doses of LPS, and IL‐1β and analgesia at larger doses. Our behavioral and electrophysiological studies have revealed that IL‐1β in the brain induces hyperalgesia through the actions of prostaglandin E2 (PGE2) on EP3 receptors in the preoptic area and its neighboring basal forebrain, whereas the IL‐1β‐induced analgesia is produced by the actions of PGE2 on EP1 receptors in the ventromedial hypothalamus. An intravenous injection of LPS (10‐100 μg/kg) produced hyperalgesia only during the period before fever develops and was abolished by microinjection of NS‐398 (an inhibitor of cyclooxygenase 2) into the preoptic area, but not into the other areas in the hypothalamus. The hyperalgesia induced by the cytokines PGE2 and LPS may explain the systemic hyperalgesia clinically observed in the early phase of infectious diseases, which probably warns the organisms of infection before the full development of sickness symptoms. The switching of nociception from hyperalgesia to analgesia accompanied by sickness symptoms may reflect changes in the hosts strategy for fighting microbial invasion as the disease progresses.

Intracerebroventricular Injection of Tumor Necrosis Factor-αInduces Thermal Hyperalgesia in Rats

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) in the brain in nociception, we injected recombinant human TNF-alpha (rhTNF-alpha; 1 pg-10 ng/rat) into the lateral cerebroventricle (LVC) in rats and observed the changes in paw withdrawal latency to radiant heat by using the plantar test for 90 min after injection. LCV injections of TNF-alpha at doses of 10 pg, 100 pg and 1 ng reduced paw withdrawal latency, showing a maximal response at a dose of 10 pg which peaked 60 min after injection. TNF-alpha at doses of 1 pg and 10 ng had no effect on nociception during the test period. The TNF-alpha (10 pg)-induced reduction in paw withdrawal latency was blocked by simultaneous injection of diclofenac (1 ng), a cyclooxygenase inhibitor, or interleukin-1 receptor antagonist (IL-1 ra, 10 ng). LCV injection of neither diclofenac (1 ng) nor IL-1 ra (10 ng) had any effect on nociception by itself. The results suggest that TNF-alpha in the brain induces thermal hyperalgesia and that the brain TNF-alpha-induced hyperalgesia is mediated by the central action of interleukin-1 and activation of the cyclooxygenase pathway of the arachidonate.

Prostaglandin E2 may induce hyperthermia through EP1 receptor in the anterior wall of the third ventricle and neighboring preoptic regions.

We have previously reported that intracerebroventricular injection of prostaglandin E2 (PGE2) induces hyperthermia possibly through EP1 receptors in the rat. In the present study, to determine the sites in the brain where PGE2 induces hyperthermia through EP1 receptors, we microinjected an EP1 receptor agonist, 17-phenyl-omega-trinor PGE2 (17-Ph-PGE2, 100 ng) into different sites in the rat brain and observed the colonic temperature (Tco) for 2 h in a 23 +/- 1 degrees C environment. Responsive sites where 17-Ph-PGE2 (100 ng) produced a rise in the Tco of more than 1.1 degrees C within 60 min after injection were found in the medial preoptic area, the subchiasmatic portion of the median preoptic nucleus, the anterior wall of the third ventricle (A3V) and the ventral portion of the diagonal band of Broca. Among these sites, the A3V was the most responsive. In contrast, microinjection of neither butaprost (an EP2 agonist, 100 ng) nor M&B28767 (an EP3 agonist, 100 ng) into these four sites had any effect on the Tco. Intracerebroventricular pretreatment with SC-19220 (an EP1 antagonist, 100 microg) inhibited the rise in the Tco which was induced by microinjection of PGE2 (50 ng) into the A3V. These results thus suggest that PGE2 induces hyperthermia by stimulating EP1 receptors in the A3V and the neighboring preoptic region.

Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats

To determine which prostaglandin E2 (PGE2) receptor subtypes are involved in the brain-derived PGE2-induced changes in nociception, we injected synthetic EP1, EP2 and EP3 receptor agonists (0.01 fmol to 10 nmol) into the lateral cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The enhancement and suppression of the nociceptive responses of the WDR neurons were observed after the LCV injection of MB28767 (an EP3 receptor agonist) at a low dose range (1-100 fmol) and 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist) at high doses (1-10 nmol), respectively. Furthermore, the suppression of nociceptive neuronal responses after the LCV injection of PGE2 (1 nmol) was completely blocked by SC19220 (an EP1 receptor antagonist, 300 nmol). On the other hand, butaprost (an EP2 receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl-omega-trinor PGE2 (1 nmol), which respectively enhanced and suppressed the nociceptive neuronal responses, did not affect the responses of the low threshold mechanoreceptive neurons to innocuous tactile stimuli. These results provide electrophysiological evidence that brain-derived PGE2 induces mechanical hyperalgesia and hypoalgesia through EP3 and EP1 receptors, respectively, in the rat.

PGE2 receptor subtype EP1 antagonist may inhibit central interleukin-1β-induced fever in rats

We have previously reported that central injection of PGE2 induces hyperthermia through its actions on EP1 receptors in rats. Because the increase in local synthesis of PGE2 is assumed to be a necessary process in a fever caused by central injection of interleukin-1β (IL-1β), an EP1 receptor antagonist (SC-19220) should inhibit the IL-1β-induced fever. To test this hypothesis, we observed the effect of SC-19220 on the fever produced by injection of recombinant human IL-1β (rhIL-1β) into the lateral cerebroventricle (LCV) in conscious rats. Administration of SC-19220 (100 μg) into the LCV 15 min before LCV injection of rhIL-1β (4 ng) suppressed an initial rise in colonic temperature for 30 min, producing a fever with a longer latency to onset and a longer time to peak elevation. SC-19220, given 60 min after the central administration of rhIL-1β, also suppressed the rhIL-1β-induced fever 15-60 min after its injection. These findings suggest that the central IL-1β-induced fever in rats is mediated, at least partly, by activation of EP1 receptors by PGE2.

Inhibition of peripheral interleukin-1β-induced hyperalgesia by the intracerebroventricular administration of diclofenac and α-melanocyte-stimulating hormone

The present study was undertaken to investigate whether or not the endogeneous mechanisms in the brain can modulate the changes in nociception produced by peripherally-administered interleukin-1 beta (IL-1 beta) in rats. We administered diclofenac and alpha-melanocyte-stimulating hormone (alpha-MSH) into the lateral cerebroventricle (LCV) 10 min before the intraperitoneal (i.p.) injection of recombinant human IL-1 beta (rhIL-1 beta, 1 ng/kg-100 ng/kg) and then observed the changes in nociception using a hot-plate test. The i.p. injection of rhIL-1 beta (10 ng/kg and 100 ng/kg) reduced the paw-withdrawal latency without affecting the colonic temperature. The maximal reduction in the paw-withdrawal latency was observed 30 min after the i.p. injection of rhIL-1 beta at 100 ng/kg. The rhIL-1 beta (100 ng/kg)-induced hyperalgesia was inhibited by the LCV injection of both diclofenac (1 ng) and alpha-MSH (100 ng). The LCV injection of either diclofenac (1 ng) or alpha-MSH (100 ng) was found to have no effect on nociception by itself. These findings therefore suggest that the hyperalgesia induced by peripheral IL-1 beta can be modulated by a cyclooxygenase pathway of the arachidonate and alpha-MSH in the brain.

Biphasic alteration in the trigeminal nociceptive neuronal responses after intracerebroventricular injection of prostaglandin E2 in rats

To investigate the role of prostaglandin E2 (PGE2) in the brain in nociception electrophysiologically, we injected PGE2 (0.1 fmol(-1) nmol) into the lateral cerebroventricle (LCV) of anesthetized rats and observed the changes of the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The LCV injection of PGE2 at 1 fmol and 10 fmol enhanced the responses of the majority of WDR neurons to noxious stimuli, whereas that of PGE2 at 100 pmol and 1 nmol suppressed them. The enhancement and suppression of the nociceptive responses of WDR neurons were observed 15-25 min and 5-15 min after injection of PGE2 at 10 fmol (3.53 pg) and 1 nmol (353 ng), respectively. On the other hand, the LCV injection of PGE2 at both 10 fmol and 1 nmol had no effect on the responses of the low threshold mechanoreceptive neurons to skin brushing. These results provide electrophysiological evidence that brain-derived PGE2 has biphasic effects on nociception, i.e., it induces mechanical hyperalgesia at lower doses and hypoalgesia at higher doses in rats.