Takakazu 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-1β induces hyperalgesia in rats

To determine whether interleukin-1 beta (IL-1 beta) in the brain may modulate nociception, recombinant human IL-1 beta (rhIL-1 beta) (1 pg/kg to 1 microgram/kg) was microinjected into the lateral cerebral ventricle of rats and the latency before initiating the licking of their hindpaws after being placed on a hot plate (50.0 +/- 0.1 degrees C) was measured. A significant reduction of the paw-lick latency was observed after injections of nonpyrogenic doses (10 pg/kg to 1 ng/kg) of rhIL-1 beta, showing a maximal response at a dose of 100 pg/kg which began to appear 5 min after injection, reached a peak within 30 min and then gradually subsided. An increase in the amount of rhIL-1 beta to > 1 ng/kg (up to 1 microgram/kg) had no effect on the nociceptive threshold. The rhIL-1 beta-induced hyperalgesia was completely abolished by pretreatment with an IL-1 receptor antagonist (IL-1ra) or Na salicylate. Similar pretreatment with alpha-melanocyte-stimulating hormone (alpha-MSH) also inhibited the rhIL-1 beta-induced hyperalgesia. However, pretreatment with alpha-helical corticotropin-releasing factor (CRF)9-41 failed to affect it. The results suggest that IL-1 beta in the brain produces hyperalgesia by its receptor-mediated and prostaglandin-dependent action which is sensitive to alpha-MSH. The hyperalgesic action of central IL-1 does not appear to depend on the CRF system.

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.

Intracerebroventricular injection of interleukin-1β enhances nociceptive neuronal responses of the trigeminal nucleus caudalis in rats

To assess the effect of interleukin-1 (IL-1) in the brain on nociception electrophysiologically, recombinant human IL-1 beta (rhIL-1 beta) (1 pg/kg to 1 microgram/kg, i.e., 0.29 pg-0.33 microgram/rat) was microinjected into the lateral cerebral ventricle of urethane-anesthetized rats and the changes of responses in the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin were observed. A significant enhancement in the responses of the WDR neurons to noxious stimuli was observed after the injection of rhIL-1 beta between 10 pg/kg and 1 ng/kg, which showed a maximal response at a dose of 100 pg/kg (29-33 pg/rat) which began to appear 5 min after injection, reached a peak within 25 min and then gradually subsided. However, this dose of rhIL-1 beta did not affect the responses of low threshold mechanoreceptive neurons to skin brushing. An increase in the dose of rhIL-1 beta by more than 10 ng/kg (up to 1 microgram/kg) had no effect on the nociceptive responses of the WDR neurons. The rhIL-1 beta-induced enhancement of nociceptive responses of WDR neurons was completely abolished by pretreatment with either IL-1 receptor antagonist, Na salicylate or alpha-melanocyte stimulating hormone. These results therefore provide electrophysiological evidence that IL-1 beta which is produced in the brain induces hyperalgesia in the rat.

Intracerebroventricular injection of prostaglandin E2 induces thermal hyperalgesia in rats: the possible involvement of EP3 receptors

To determine what types of prostanoid receptors are involved in the central effect of prostaglandin E2 (PGE2) on nociception, we administered PGE2 and its agonists, i.e., 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist), butaprost (an EP2 receptor agonist), 11-deoxy PGE1 (an EP2/EP3 receptor agonist, EP2 >> EP3) and M&B28767 (an EP3 receptor agonist) into the lateral cerebroventricle (LCV) of rats and observed the changes of paw-withdrawal latency on a hot plate. The LCV injection of PGE2 (10 pg/kg-10 ng/kg), 11-deoxy PGE1 (100 pg/kg-10 ng/kg) and M&B28767 (1 pg/kg-100 pg/kg) produced a significant reduction in the paw-withdrawal latency. The maximal reduction was observed 15 min after the LCV injection of these drugs. Neither 17-phenyl-omega-trinor PGE2 (1 pg/kg-1 microgram/kg) nor butaprost (1 pg/kg-100 microgram/kg) induced any significant changes in the paw-withdrawal latency. The LCV injection of PGE2 (1 microgram/kg) and 17-phenyl-omega-trinor PGE2 (50 micrograms/kg) increased the latency only 5 min after LCV injection. These findings indicate that the LCV injection of PGE2 induces thermal hyperalgesia through EP3 receptors and analgesia through EP1 receptors by its central action in rats.

Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa

Previous investigations have suggested that ghrelin, an endogenous orexigenic peptide, is involved in the pathology of eating disorders. We conducted a study to determine whether any preproghrelin gene polymorphisms are associated with eating disorders. Three hundred thirty‐six eating disorder patients, including 131 anorexia nervosa (AN)‐restricting types (AN‐R), 97 AN‐binge eating/purging types (AN‐BP) and 108 bulimia nervosa (BN)‐purging types (BN‐P), and 300 healthy control subjects participated in the study. Genotyping was performed to determine the polymorphisms present, and with this information, linkage disequilibrium (LD) between the markers was analyzed and the distributions of the genotypes, the allele frequencies, and the haplotype frequencies were compared between the groups. The Leu72Met (408 C > A) (rs696217) polymorphism in exon 2 and the 3056 T > C (rs2075356) polymorphism in intron 2 were in LD (D′ = 0.902, r2 = 0.454). Both polymorphisms were significantly associated with BN‐P (allele‐wise: P = 0.0410, odds ratio (OR) = 1.48; P = 0.0035, OR = 1.63, for Leu72Met and 3056 T > C, respectively). In addition, we observed a significant increase in the frequency of the haplotype Met72‐3056C in BN‐P patients (P = 0.0059, OR = 1.71). Our findings suggest that the Leu72Met (408 C > A) and the 3056 T > C polymorphisms of the preproghrelin gene are associated with susceptibility to BN‐P.

Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region

Psychological stress‐induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0 °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non‐shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase‐positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress‐induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β3‐adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress‐induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3‐expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β3‐adrenoreceptors.

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.