Effects of peripheral administration of a Neuromedin U receptor 2-selective agonist on food intake and body weight in obese mice.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity. METHODS: Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain. RESULTS: We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS. CONCLUSION: Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.

Natural variation in light sensitivity of Arabidopsis.

Because plants depend on light for growth, their development and physiology must suit the particular light environment. Plants native to different environments show heritable, apparently adaptive, changes in their response to light. As a first step in unraveling the genetic and molecular basis of these naturally occurring differences, we have characterized intraspecific variation in a light-dependent developmental process-seedling emergence. We examined 141 Arabidopsis thaliana accessions for their response to four light conditions, two hormone conditions and darkness. There was significant variation in all conditions, confirming that Arabidopsis is a rich source of natural genetic diversity. Hierarchical clustering revealed that some accessions had response patterns similar to known photoreceptor mutants, suggesting changes in specific signaling pathways. We found that the unusual far-red response of the Lm-2 accession is due to a single amino-acid change in the phytochrome A (PHYA) protein. This change stabilizes the light-labile PHYA protein in light and causes a 100-fold shift in the threshold for far-red light sensitivity. Purified recombinant Lm-2 PHYA also shows subtle photochemical differences and has a reduced capacity for autophosphorylation. These biochemical changes contrast with previously characterized natural alleles in loci controlling plant development, which result in altered gene expression or loss of gene function.

Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population.

OBJECTIVES: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. METHODS: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. RESULTS: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. CONCLUSIONS: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study.

Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer's Disease Neuroimaging Initiative Database.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) has been reported to be correlated with declines in hippocampal volume and cognitive function in ApoE4-positive MCI patients. OBJECTIVES: The present study was aimed to investigate the effects of plasma matrix MMP-9 on the conversion risk between mild cognitive impairment (MCI) patients with and without ApoE4. DESIGN AND SETTING: Retrospective observational study using the data extracted from the Alzheimer's Disease Neuroimaging Initiative database. PARTICIPANTS: We included 211 ApoE4-positive MCI subjects (ApoE4+ MCI) and 184 ApoE4-negative MCI subjects (ApoE4- MCI). MEASUREMENTS: We obtained demographic and data including plasma MMP-9 levels at baseline and longitudinal changes in Clinical Dementia Rating (CDR) up to 15 years. We compared conversion rates between ApoE4+ MCI and ApoE4- MCI by the Log-rank test and calculated the hazard ratio (HR) for covariates including age, sex, educational attainment, drinking and smoking histories, medications, and plasma MMP-9 levels using a multiple Cox regression analysis of ApoE4+ MCI and ApoE4- MCI. RESULTS: No significant differences were observed in baseline plasma MMP-9 levels between ApoE4+ MCI and ApoE4- MCI. High plasma MMP-9 levels increased the conversion risk significantly more than low plasma MMP-9 levels (HR, 2.46 [95% CI, 1.31-4.48]) and middle plasma MMP-9 levels (HR, 1.67 [95% CI, 1.04-2.65]) in ApoE4+ MCI, but not in ApoE4- MCI. CONCLUSION: Plasma MMP-9 would be the risk of the future conversion to dementia in ApoE4+ MCI.

A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes.

AIM: To examine the efficacy, safety and tolerability of rivoglitazone, a novel thiazolidinedione (TZD), and explore its effects on glucose and lipid control compared to placebo and pioglitazone in Chinese type 2 diabetic patients who are treatment naÏve or treated with a single oral blood glucose-lowering drug. METHODS: This was a double-blind, randomized, placebo- and active-controlled study. A total of 287 Chinese type 2 diabetic patients with suboptimal glycaemic control (defined as HbA1c ≥6.5 to <10% and fasting plasma glucose ≥7 to ≤15 mmol/l) were enrolled. One hundred and seventy-four eligible patients were randomized into one of the five treatment arms for 12 weeks: placebo, pioglitazone 30 mg daily, rivoglitazone of dose 0.5, 1.0 or 1.5 mg daily. In a full set analysis, we used analysis of covariance to compare the primary endpoint defined as change in HbA1c from baseline to week 12/last observation carried forward in the rivoglitazone group at each dose level with the placebo group. RESULTS: Changes in HbA1c were -0.11% in the 0.5-mg group; -0.22% in the 1-mg group and -0.17% in the 1.5-mg rivoglitazone group; -0.06% in the 30-mg pioglitazone group and 0.61% in the placebo group. Compared to placebo, changes were significant in all active treatment groups (all p < 0.05). Increase in high-density lipoprotein cholesterol and decrease in triglyceride were observed in the rivoglitazone 1 and 1.5 mg groups, respectively, compared to placebo from baseline to week 12 (p < 0.05). Drug-related oedema was reported in eight patients (7.7%) in all rivoglitazone groups compared to six patients (16.2%) in the pioglitazone group and one patient (3.0%) in the placebo group. CONCLUSIONS: Rivoglitazone is an efficacious, safe and well-tolerated TZD which improved glycaemic control in Chinese type 2 diabetic patients up to 3 months.

Enantiomorphs differ in shape in opposite directions between populations.

Development is left-right reversed between dextral and sinistral morphs of snails. In sympatry, they share the same gene pool, including polygenes for shell shape. Nevertheless, their shell shapes are not the mirror images of each other. This triggered a debate between hypotheses that argue either for a developmental constraint or for zygotic pleiotropic effects of the polarity gene. We found that dextrals can be wider or narrower than sinistrals depending on the population, contrary to the prediction of invariable deviation under a developmental constraint. If the pleiotropy is solely responsible instead, the mean shape of each morph should change, depending on the frequency of polarity genotype. Our simulations of this mean shape change under zygotic pleiotropy, however, show that the direction of interchiral difference remains the same regardless of genotype frequency. Our results suggest the presence of genetic variation among populations that changes the maternal or zygotic pleiotropic effect of the polarity gene.

Multicenter observational study comparing sedation/analgesia protocols for laser photocoagulation treatment of retinopathy of prematurity.

OBJECTIVE: The aim of this study was to identify the best sedation/analgesia protocol for laser photocoagulation (PC) of retinopathy of prematurity (ROP). STUDY DESIGN: This multicenter observational study included five hospitals, each using a specific sedation/analgesia protocol: local anesthesia with oxybuprocaine hydrochloride (Group L); intravenous pentazocine (Group P); intravenous fentanyl (Group F); air, oxygen and sevoflurane (AOS) inhalation (Group I). The groups were compared for pain responses, vital signs and adverse events. RESULTS: Heart rates and systemic blood pressures were elevated by PC in Groups L and P and Groups L, P and F, respectively. Moreover, poor analgesic efficacy was recognized in Groups L, P and F. In contrast, Group I experienced hypothermia, enteral feeding intolerance and apnea more frequently. CONCLUSION: From the viewpoint of sedation/pain relief, AOS anesthesia should be the best protocol. However, considering all the various factors together, the most reasonable one can be varied based on the patient's condition and hospital.

Responses of anterior hypothalamic-preoptic thermosensitive neurons to substance P and capsaicin.

The effects of capsaicin and substance P, applied locally, on the activity of thermosensitive and thermally-insensitive neurons in the anterior hypothalamic-preoptic area were studied with the use of multibarrelled microelectrodes in the urethane-anesthetized rat. In a total of 34 thermosensitive neurons (21 warm-units and 13 cold-units) in the anterior hypothalamic-preoptic area, only 7 units responded to substance P and 27 units (79.4%) were not affected. In contrast, 23 of 57 (40.4%) thermally-insensitive neurons responded to substance P. Of 74 thermosensitive and thermally-insensitive neurons tested with both substance P and capsaicin, only 7 units (9.5%) showed the same direction of change in activity in response to the application of both drugs. The majority of the neurons responded to only one of the drugs (32 units, 43.2%) or responded to substance P and capsaicin in opposite directions (9 units, 12.2%). A substance P antagonist, (D-Pro2, D-Trp7,9)-substance P, blocked the substance P-induced excitatory responses in 5 of 6 neurons tested in the anterior hypothalamic-preoptic area, but not the capsaicin-induced excitatory or inhibitory responses (n = 5). It is unlikely that substance P in the anterior hypothalamic-preoptic area participates in the hypothermic effects of capsaicin, observed after local injection.

Responses of anterior hypothalamic-preoptic thermosensitive neurons to thyrotropin releasing hormone and cyclo(His-Pro).

Effects of local application of thyrotropin releasing hormone (TRH) and its metabolite, histidyl-proline diketopiperazine [cyclo (His-Pro)], on the activity of thermosensitive and thermally-insensitive neurons of the anterior hypothalamic-preoptic area were investigated in urethane-anesthetized rats. Microelectrophoretic application of TRH changed the activity of 126 of 206 neurons tested. Thyrotropin releasing hormone predominantly decreased the activity of warm-sensitive neurons and increased the activity of cold-sensitive neurons. Since it has been generally assumed that warm-sensitive and cold-sensitive neurons in the anterior hypothalamic-preoptic area mediate heat and cold defence responses, respectively, the present results are consistent with previous findings showing hyperthermia after injection of TRH into the hypothalamus in the rat. Cyclo (His-Pro) affected the activity of 59 of 153 neurons tested. In addition, cyclo (His-Pro) did not preferentially affect warm- or cold-sensitive neurons. These results indicate that the previously-determined hypothermic effect of cyclo (His-Pro) cannot be explained by its effects on thermosensitive neurons in the anterior hypothalamic-preoptic area.

Endothelin-1 analogues substituted at both position 18 and 19: highly potent endothelin antagonists with no selectivity for either receptor subtype ETA or ETB.

Novel endothelin-1 (ET-1) analogues which are highly potent endothelin antagonists at both receptor subtype ETA and ETB are reported. The replacement of Asp18 with the Thr18 and of Ile19 with a hydrophobic amino acid whose side-chain branches on the gamma-carbon such as Leu, cyclohexylalanine, and gamma-methylleucine (gamma-MeLeu) resulted in loss of or significantly decreased the biological activity of ET-1, while high affinity for the ETA (IC50 = 0.42-0.70 nM) and ETB (IC50 = 0.17-0.43 nM) receptor was retained. These compounds were shown to have high antagonist activities in ET-1-induced vasoconstriction of porcine coronary artery (pA2 7.4-7.7) and in Sarafotoxin S6c-induced vasoconstriction of rabbit pulmonary artery ([Thr18, gamma-MeLeu19]ET-1: pA2 8.4). Among these compounds, [Thr18, gamma-MeLeu19]ET-1 has the desirable characteristic of possessing no agonist activity at either receptor subtype.

Endogenous neurotrophin-3 is retrogradely transported in the rat sciatic nerve.

To address the active transport of neurotrophins, nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 in the peripheral nerves, we examined the levels of proteins and messenger RNAs in the sciatic nerve of adult rats following transection, using enzyme immunoassays and reverse transcription polymerase chain reaction method, respectively. Neurotrophin-3 protein increased one day after transection only in the distal segment next to the transection site and returned to the original level two days later. This was considered to reflect accumulation of neurotrophin-3 transported from the periphery toward the neuronal cell bodies, because the neurotrophin-3 messenger RNA level was not changed in any sciatic segments during this experimental period. An increase in brain-derived neurotrophic factor protein was observed simultaneously in both the distal and proximal stumps three days after transection. Brain-derived neurotrophic factor messenger RNA was elevated in the same stumps two days after transection, suggesting that brain-derived neurotrophic factor was produced within the transected stumps. These observations demonstrate that neurotrophin-3, like nerve growth factor, is retrogradely transported in the sciatic nerve but that brain-derived neurotrophic factor is not. This suggests that neurotrophin-3 plays a role in the conveyance of trophic signals from target organs to neurons.

Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine.

The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine , increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3-4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1-1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D2 antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.

Changes in serum apolipoprotein concentrations after L-thyroxine therapy in infants with congenital hypothyroidism.

To further characterize the impact of thyroid hormones on the serum lipid profile, we studied serum apolipoproteins in infants with congenital hypothyroidism before and after L-thyroxine (L-T4) replacement therapy. Serum high-density lipoprotein cholesterol (HDLC) decreased after L-T4 therapy. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels did not change significantly after therapy. Two months after L-T4 replacement therapy, serum apolipoprotein A-I (apo A-I), C-III, and E declined and apo B increased significantly. No significant changes were observed for serum concentrations of apo A-II and C-II after L-T4 substitution. We conclude that in infants, thyroid hormone reduces serum levels of apo A-I, the principal protein component of HDLC, and this may contribute to the decline of serum HDLC concentrations after L-T4 replacement therapy.

Plasma cholesteryl ester transfer protein activity is high in infants and is not affected by thyroid hormones.

We investigated the effects of thyroid dysfunction on cholesteryl ester transfer protein (CETP) by studying plasma CETP activity in hypothyroid infants before and after they were rendered euthyroid by L-thyroxine (LT4) replacement therapy. To exclude environmental factors possibly affecting plasma CETP activity, we selected hypothyroid infants to study plasma CETP activity. Plasma CETP activity was measured as the rate of radiolabeled cholesteryl ester transfer from high-density lipoprotein (HDL) to serum apolipoprotein B (apo B)-containing lipoproteins in plasma from 14 hypothyroid infants before and 2 months after LT4 replacement, 23 normal infants, and 61 normal adults. Relationships between CETP and thyroid hormones were examined separately in the 14 hypothyroid infants and 32 euthyroid infants, including the 14 above-described hypothyroid infants and an additional 18 treated hypothyroid infants. Serum levels of thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were also determined on an autoanalyzer system in our hospital. In contrast to previous reports, we found no differences in plasma CETP activity between hypothyroid infants and age-matched normal infants. LT4 substitution did not cause any changes in plasma CETP activity after therapy. Plasma CETP activity showed no correlation with serum TSH, FT4, and FT3 levels. Both hypothyroid and normal infants were found to have significantly higher plasma CETP activity than normal adults. From these results, we conclude that in infants thyroid hormones do not affect plasma CETP activity, and normal infants have high plasma CETP activity, compared with normal adults.

Zinc ion enhances the blocking potency of synthetic analogs of spider toxin (JSTX) on the glutamate receptor.

The effect of synthetic spider toxin analogs containing aza-crown in combination with zinc and copper was studied on the lobster neuromuscular synapse. The suppressive action of N4-type spider toxin analog (N4) on excitatory postsynaptic potentials (EPSPs) was markedly enhanced in the presence of 10(-5)-10(-4) M Zn2+. Cu2+ (10(-4) M) also had a potentiating effect on the suppression of EPSPs by N4 but to a lesser degree than Zn2+. While N6-type spider toxin analog (N6) suppressed EPSPs more effectively than N4, additional suppression was not pronounced in the presence of Zn2+ or Cu2+. The results suggest that chelatable divalent metal ions play an important role in the blocking mechanism of glutamate receptor by the spider toxin.

Intravenous self-administration of diazepam in rats.

Diazepam 0.5-2.0 mg/kg per injection was self-administered intravenously by rats on a continuous reinforcement schedule in a dose-dependent manner over a 30 day period. The rates of diazepam self-administration were relatively stable after responding was established, in comparison with rats self-administering morphine 0.5 mg/kg per injection whose rates continued to increase. At a fixed ratio 4 or 8 schedule, higher maximum rates of responding were seen with diazepam than with morphine. During withdrawal, reductions in body weight tended to occur in a manner dependent on the preceding rates of diazepam self-administration and were possibly caused by physical dependence. These findings suggest that diazepam acts as an intravenous reinforcer in rats and that the procedure we describe is of use to predict the dependence liability of drugs considered to have only a weak potential for abuse.

Vitreoretinal traction maculopathy caused by retinal diseases.

PURPOSE: To study the morphological findings of vitreoretinal traction maculopathy caused by retinal vascular diseases and their changes after vitrectomy. METHODS: Optical coherence tomographic images of 13 eyes of 12 cases were evaluated before and after vitrectomy. RESULTS: The tractional force appeared to be mainly tangential with a possible anterior vector in 11 eyes, and mainly in the anterior direction in 2 eyes. After surgery, the increased foveal thickness decreased markedly in all eyes, and visual acuity improved in 8 eyes. CONCLUSION: Preoperative optical coherence tomographic examination can reveal the fine structure of vitreoretinal separations and adherences caused by retinal vascular diseases. These observations permitted better surgical planning and results.

Convergence of thermal signals on the reticulospinal neurons in the midbrain, pons and medulla oblongata.

A total of 670 reticulospinal (RfS) and non-RfS neurons in the mesencephalic, pontile and medullary reticular formation (mRf, pRf and mdRf) were studied for the responsiveness to changes in temperatures of local brain sites, preoptic and anterior hypothalamus (PO/AH) and skin in the urethane anesthetized rat. Local thermoresponsiveness was found in 49.6% of 139 mRf neurons, 61.9% of 160 pRf neurons and 75.4% of 126 mdRf neurons. While the ventromedial region of pRf and mdRf contained predominantly warm-responsive neurons (54.8% and 62.5%), cold-responsive neurons were much more frequently found in the mRf (33.8%) and the dorsolateral region of pRf (41.9%) and mdRf (50.0%). Responsiveness to hypothalamic temperature and/or skin temperature was observed in about 40-74% of Rf neurons. Higher incidence of responsiveness to remote temperatures was found among locally thermoresponsive neurons than among locally thermounresponsive neurons in all three areas. Particularly, there was a high degree of convergence of 'cold' signals from local and remote sites on the RfS neurons in the mRf and the dorsolateral pRf and mdRf. Microinjections of procaine and glutamate into these regions decreased and increased the cold-induced increase in EMG activity and shivering without any correlated changes in cardiovascular and respiratory parameters and pilomotor activity. The results suggest that RfS and non-RfS neurons in the mRf and the dorsolateral pRf and mdRf are involved in the control of thermoregulatory muscle tone and shivering.

Thermally-induced activities of the mesencephalic reticulospinal and rubrospinal neurons in the rat.

Unit activities of 226 midbrain reticulospinal (mRfS) and non-mRfS neurons and 238 rubrospinal (RbS) and non-RbS neurons were investigated during changes in temperatures of midbrain (Tmb), preoptic and anterior hypothalamus (Thyp) and skin (Ts) in the urethane-anesthetized rat. Responsiveness to Tmb, Thyp and Ts were found in 43.5%, 41.6% and 51.5% of neurons of midbrain reticular formation (mRf), and in 35.2%, 32.7% and 17.6% of neurons of red nucleus (Rb). Higher incidence of responsiveness to remote temperatures was found among Tmb responsive neurons than Tmb unresponsive neurons in both mRf and Rb. The mRf contains significantly greater numbers of neurons having such multiple thermal responsiveness and also of neurons which were activated by falls in temperatures (cold-responsive neurons) than the Rb. These characteristics were more conspicuously seen among mRfS neurons, showing a high degree of convergence of cold signals from different sites of body. On the other hand, RbS neurons did not differ from non-RbS neurons regarding thermal characteristics and showed no particular combinations of responsiveness to temperatures of different sites. Microinjection of procaine and glutamate into the mRf just dorsolateral to the Rb, but not into the Rb, decreased and increased cold-induced increase in EMG activity and shivering without changes in cardiovascular and respiratory parameters and pilomotor activity. The results suggest that mRfS neurons are involved in the control of thermoregulatory muscle tone and shivering.

Effects of interleukin-1 and arachidonate on the preoptic and anterior hypothalamic neurons.

Effects of microelectrophoretic application of ultrapure human interleukin-1 (IL-1), an endogenous pyrogen, on the activity of 80 neurons in the preoptic and anterior hypothalamus (PO/AH) were investigated in the urethane anesthetized rat. IL-1 predominantly decreased the activity of warm-sensitive neurons (15 of 19) and increased the activity of cold-sensitive neurons (10 of 12), but had no effect on 37 of 49 thermally insensitive neurons. The neuronal responses to IL-1 were blocked or attenuated by concurrent application of mepacrine (a phospholipase inhibitor) or sodium salicylate (a cyclooxygenase inhibitor). Local application of sodium arachidonate decreased the activity in 17 of 28 warm-units and excited 12 of 16 cold-units, and the effects of arachidonate were blocked by sodium salicylate. The results are compatible with the view that one or more cyclooxygenase metabolites of arachidonic acid are involved in the IL-1 induced fever.