Regulatory mechanism of body temperature in the central nervous system during the maintenance phase of hibernation in Syrian hamsters: involvement of ß-endorphin.

We have shown previously that intracerebroventricular (icv) injection of naloxone (a non-selective opioid receptor antagonist) or naloxonazine (a selective µ1-opioid receptor antagonist) at the maintenance phase of hibernation arouses Syrian hamsters from hibernation. This study was designed to clarify the role of ß-endorphin (an endogenous µ-opioid receptor ligand) on regulation of body temperature (T(b)) during the maintenance phase of hibernation. The number of c-Fos-positive cells and ß-endorphin-like immunoreactivity increased in the arcuate nucleus (ARC) after hibernation onset. In contrast, endomorphin-1 (an endogenous µ-opioid receptor ligand)-like immunoreactivity observed on the anterior hypothalamus decreased after hibernation onset. In addition, hibernation was interrupted by icv injection of anti-ß-endorphin antiserum at the maintenance phase of hibernation. The mRNA expression level of proopiomelanocortin (a precursor of ß-endorphin) on ARC did not change throughout the hibernation phase. However, the mRNA expression level of prohormone convertase-1 increased after hibernation onset. [D-Ala2,N-MePhe4,Gly-ol5] enkephalin (DAMGO, a selective µ-opioid receptor agonist) microinjection into the dorsomedial hypothalamus (DMH) elicited the most marked T(b) decrease than other sites such as the preoptic area (PO), anterior hypothalamus (AH), lateral hypothalamus (LH), ventromedial hypothalamus and posterior hypothalamus (PH). However, microinjected DAMGO into the medial septum indicated negligible changes in T(b). These results suggest that ß-endorphin which synthesizes in ARC neurons regulates T(b) during the maintenance phase of hibernation by activating µ-opioid receptors in PO, AH, VMH, DMH and PH.

Protective effects of radon inhalation on carrageenan-induced inflammatory paw edema in mice.

We assessed whether radon inhalation inhibited carrageenan-induced inflammation in mice. Carrageenan (1% v/v) was injected subcutaneously into paws of mice that had or had not inhaled approximately 2,000 Bq/m(3) of radon for 24 h. Radon inhalation significantly increased superoxide dismutase (SOD) and catalase activities and significantly decreased lipid peroxide levels in mouse paws, indicating that radon inhalation activates antioxidative functions. Carrageenan administration induced paw edema and significantly increased tumor necrosis factor-alpha (TNF-α) and nitric oxide in serum. However, radon inhalation significantly reduced carrageenan-induced paw edema. Serum TNF-α levels were lower in the radon-treated mice than in sham-treated mice. In addition, SOD and catalase activities in paws were significantly higher in the radon-treated mice than in the sham-treated mice. These findings indicated that radon inhalation had anti-inflammatory effects and inhibited carrageenan-induced inflammatory paw edema.

Beneficial action of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one, a novel long-chain fatty alcohol, on diabetic hypoalgesia and neuropathic hyperalgesia.

The effects of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one (tCFA15) on diabetic hypoalgesia and neuropathic hyperalgesia were examined. Treatments of streptozotocin (STZ)-pretreated mice with tCFA15 (8 - 40 mg/kg, i.p.) for 7 days significantly reversed the depressed inflammatory nociceptive licking response in the formalin test. In addition, similar drug treatments and dosing in 7-day postoperative neuropathic pain model rats (prepared by the method of Bennett and Xie) yielded a similarly favorable outcome by significantly reversing decreased nociceptive thresholds in the paw pressure test. These results suggest that tCFA15 may have the potential to normalize sensory nerve abnormalities induced in experimental diabetes and nerve injury.

Neuroprotective effects of hibernation-regulating substances against low-temperature-induced cell death in cultured hamster hippocampal neurons.

The neuroprotective effects of hibernation-regulating substances (HRS) such as adenosine (ADO), opioids, histamine and thyrotropin-releasing hormone (TRH) on low-temperature-induced cell death (LTCD) were examined using primary cultured hamster hippocampal neurons. LTCD was induced when cultures were maintained at <22 degrees C for 7 days. ADO (10-100 microM) protected cultured neurons from LTCD in a dose-dependent manner. The neuroprotective effects of ADO were reversed by both 8-cyclopenthyltheophilline (CPT; A(1) receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (DMPX; A(2) receptor antagonist). Morphine (a non-selective opioid receptor agonist) was also effective in attenuating LTCD at an in vitro dose range of 10-100 muM. The neuroprotective effects of morphine were antagonized by naloxone (a non-selective opioid receptor antagonist). In addition, although [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO; mu-opioid receptor agonist), [D-Pen(2,5)]-enkephalin (DPDPE; delta-opioid receptor agonist) and U-69593 (kappa-opioid receptor agonist) were also effective, LTCD of cultured hippocampal neurons was not affected by TRH. Furthermore, histamine produced hypothermia in Syrian hamsters and protected hippocampal neurons in vitro at 100 microM. The neuroprotective effect of histamine was reversed by pyrilamine (H(1) receptor antagonist). Apoptosis was probably involved in LTCD. These results suggest that ADO protected hippocampal neurons in vitro via its agonistic actions on both A(1) and A(2) receptors, whereas morphine probably elicited its neuroprotective effects via agonistic effects on the mu-, delta- and kappa-opioid receptors. In addition, histamine also protected hippocampal neurons via its agonistic action on the H(1) receptor. Thus, HRS-like adenosine-, opioid- and histamine-like hypothermic actions would most likely induce neuroprotective effects against LTCD in vitro.

Phase-specific central regulatory systems of hibernation in Syrian hamsters.

The central body temperature (T(b)) regulation system during hibernation was investigated in Syrian hamsters of either sex. Hibernation induced in Syrian hamsters by housing them in a cold room under short day-light/dark cycle was confirmed by marked reductions in the heart rate, T(b) and respiratory rate. The hibernation of hamsters was classified into (i) entrance, (ii) maintenance and (iii) arousal phases according to T(b) changes. In hibernating hamsters, T(b) elevations were phase-selectively elicited by intracerebroventricular (ICV) injection of 8-cyclopenthyltheophylline (CPT; a selective A1-adenosine receptor antagonist) and naloxone (a non-selective opioid receptor antagonist) during the entrance and maintenance phases, respectively. Moreover, a similar T(b) elevation tendency during the maintenance phase was also induced by ICV naloxonazine, (a selective mu1-opioid receptor antagonist), although such was not the case for naltrindole (a selective delta-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a selective kappa-opioid receptor antagonist). Furthermore, T(b) elevations in hibernating hamsters were similarly induced with ICV thyrotropin-releasing hormone (TRH) during the entrance and maintenance phases. Furthermore, ICV injection of the anti-TRH antibody ameliorated the T(b) elevations induced by tactile stimulation. These results suggest that activation of the A1-receptor by adenosine is important for the generation of hypothermia in the entrance phase, and that activation of the mu1-opioid receptor by opioid peptides is required for perpetuation of hypothermia in the maintenance phase. In addition, TRH is a key endogenous substance involved in T(b) elevations during the arousal phase of hibernating hamsters.

Thyrotropin-releasing hormone induced thermogenesis in Syrian hamsters: site of action and receptor subtype.

Early work in our laboratory has revealed the important role played by thyrotropin-releasing hormone (TRH) in the arousal from hibernation in Syrian hamsters. In the present study, we investigated the thermogenic mechanism of TRH in Syrian hamsters. Six to 10 female Syrian hamsters were used in the respective experiments. Intracerebroventricular (icv) injection of TRH elevated the intrascapular brown adipose tissue (IBAT) temperature (T(IBAT)) and rectal temperature (T rec) in Syrian hamsters. Thermogenic response of icv TRH was suppressed by bilateral denervation of the sympathetic nerve. Icv injection of TRH increased the norepinephrin (NE) turnover rate in IBAT without affecting the total serum triiodothyronine (T3) level. Moreover, TRH microinjections into the dorsomedial hypothalamus (DMH), preoptic area (PO), anterior hypothalamus (AH) and ventromedial hypothalamus (VMH) induced T(IBAT) and T(rec) increases. However, neither T(IBAT) nor T rec was affected by similar TRH administrations into the lateral hypothalamus and posterior hypothalamus. Interestingly, although TRH-induced hyperthermia was suppressed by pretreatment of anti-TRH-R1 antibodies, no changes were induced by anti-TRH-R2 antibodies. These results suggest that the sites of action of TRH associated with thermogenesis are probably localized in the DMH, PO, AH and VMH. In addition, TRH-induced thermogenesis is probably elicited by facilitation of the sympathetic nerve system via the central TRH-R1 irrelevant of T3.

Characterization of N(6)-cyclohexyladenosine-induced hypothermia in Syrian hamsters.

The N(6)-cyclohexyladenosine (CHA)-induced hypothermia in Syrian hamsters was characterized as follows: intracerebroventricular injection of CHA-induced hypothermia and the potency was increased by lowering the ambient temperature. CHA microinjection into the anterior hypothalamus (AH) elicited the most marked body temperature (T(b)) decrease compared with other regions such as the preoptic area, dorsomedial hypothalamus, posterior hypothalamus, and hippocampus. In contrast, microinjected CHA into the medial septum, ventromedial hypothalamus, and lateral hypothalamus resulted in negligible changes in T(b). These results suggest that CHA-induced hypothermia was probably due to suppression of thermogenesis via the site(s) of CHA action, viz., the AH and medial hypothalamus.