[Systemic inflammatory profile of smokers with and without COPD]. / Profil inflammatoire systémique des fumeurs atteints de BPCO comparés aux fumeurs indemnes de BPCO.

INTRODUCTION: Studies comparing the systemic inflammatory profiles of smokers with and without COPD present discordant findings. AIM: To compare the systemic inflammatory profile of smokers with and without COPD. METHODS: This is a cross-sectional comparative study. Two groups of active smokers of more than 10 pack-years were included: 56 consecutives stable COPD (postbronchodilator FEV1/FVC<0.70) and 32 consecutives non-COPD (postbronchodilator FEV1/FVC≥0.70). Smoking and clinical, anthropometric and spirometric data were noted. The following blood biomarkers were identified: leukocytes, hemoglobin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). According to the levels (normal/abnormal) of these markers, two groups of smokers were formed. Quantitative and qualitative data were expressed, respectively, as means±SD and percentages. RESULTS: Compared to the non-COPD group, the COPD group was older (56±12 vs. 65±8 years) and had a higher smoking consumption (30±18 vs. 52±31 pack-years). Compared to the non-COPD group, the COPD group had higher values of CRP (2.06±1.24 vs. 11.32±11.03mg/L), of ESR (9.59±8.29 vs. 15.96±11.56), of IL-6 (9.28±4.69 vs. 20.27±5.31ng/L) and of TNF-α (18.38±7.98ng/L vs. 8.62±3.72ng/L). Compared to the non-COPD group, the COPD group included higher percentages of smokers with elevated CRP (0 % vs. 32 %), with leukocytosis (6 % vs. 16 %), with higher levels of IL-6 (81 % vs. 98 %) or TNF-α (91 % vs. 100 %). CONCLUSION: Smokers with COPD, compared to smokers free from COPD, have a marked systemic inflammation.

Five cases of acute Zika virus infection in French women of reproductive age returning from Central and South America.

INTRODUCTION: The favorable season for Aedes albopictus circulation has started in Europe and may lead to autochthonous transmission of Zika virus. Health care providers should be familiar with evocative clinical presentations and able to give updated information to women of reproductive age infected by Zika virus. OBSERVATIONS: We report five laboratory-confirmed Zika virus infections imported to metropolitan France from Central and South America between January and April, 2016. The five young women were not connected and not pregnant; common presentation combined a rash with persistent arthralgia. Zika virus was identified by RT-PCR from serum or urines, between two and eight days after the onset of the symptoms. CONCLUSION: As the duration of potential materno-foetal infectivity is still unknown, we were unable to answer with certitude to the patients' questions about the time interval to respect before attempting a pregnancy: one of them became pregnant one month after the diagnosis.

Acetaminophen: a central analgesic drug that involves a spinal tropisetron-sensitive, non-5-HT(3) receptor-mediated effect.

The reversal of the antinociceptive effect of systemically administered acetaminophen (paracetamol) by intrathecal administration of the potent 5-HT(3) receptor antagonist tropisetron has been reported in rats subjected to the paw pressure test, suggesting that acetaminophen action is mediated through spinal 5-HT(3) receptors. However, more recent data, showing differences between the pharmacological profiles of various 5-HT(3) receptor antagonists, led us to reconsider the involvement of spinal 5-HT(3) receptors. To address this question, two different approaches were used: 1) electrophysiological recordings to assess whether acetaminophen directly modulates 5-HT(3) receptor activity and 2) pharmacological investigations with various 5-HT(3) receptor antagonists and spinal 5-HT(3) receptors antisense oligodeoxynucleotides (AODNs) to determine how those treatments might affect the antinociceptive action of acetaminophen. Electrophysiological studies demonstrated that acetaminophen had no direct agonist or antagonist effects on 5-HT(3A) receptors. Unlike tropisetron, other 5-HT(3) receptor antagonists, such as ondansetron and granisetron, injected intrathecally were unable to reverse the antinociceptive effect of acetaminophen. Moreover, pretreatment with AODNs did not reverse the acetaminophen-induced antinociceptive effect, although it suppressed the antinociceptive effect of m-chlorophenylbiguanide, a specific agonist of 5-HT(3) receptors, and significantly reduced (30%) the expression of these receptors in the dorsal horn of the spinal cord. These results suggest that acetaminophen-induced antinociceptive action involves a spinal tropisetron-sensitive receptor that is not the 5-HT(3) receptor and that remains to be identified.

Evidence for an involvement of supraspinal delta- and spinal mu-opioid receptors in the antihyperalgesic effect of chronically administered clomipramine in mononeuropathic rats.

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 microg/kg i.v., which selectively blocks the mu-opioid receptor, inhibited the anti-hyperalgesic effect of clomipramine and hence indicated that mu-opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP), mu; naltrindole (NTI), delta; and nor-binaltorphimine (nor-BNI), kappa] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: delta-receptors at the supraspinal level and mu-receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed.

Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats.

BACKGROUND AND AIMS: Short-chain fatty acid (SCFA) (especially butyrate) enemas are widely used to reduce symptoms associated with human inflammatory bowel disease. The purpose of this study was to evaluate their real effect on colonic sensitivity in rats. METHODS: The effects of saline and SCFA enemas (acetate, propionate and particularly butyrate) were studied on visceral pain thresholds following colonic distension in control rats and in rats with colitis (instilled with trinitrobenzene sulfonic acid (TNBS)). RESULTS: Butyrate enemas (40 mM twice daily for 14 days) decreased colonic pain thresholds in control rats; they did not reduce the TNBS-induced hypersensitivity, but on the contrary increased its duration (without modifying the inflammation score). This pronociceptive effect was confirmed in control rats receiving twice daily enemas of 80 mM for 3 days and two enemas of 240 mM of a butyrate solution. The other SCFA enemas did not modify the hypersensitivity of rats with colitis and induced proinflammatory effects. CONCLUSIONS: The beneficial effect of SCFA (especially butyrate) enemas on hypersensitivity and inflammation in inflammatory bowel disease is questionable and needs to be thoroughly investigated in humans.

5-HT receptor subtypes involved in the spinal antinociceptive effect of acetaminophen in rats.

The present study was designed to investigate which subtype of spinal 5-HT receptors were involved in acetaminophen-induced antinociception using the paw-pressure test. Propacetamol (prodrug of acetaminophen, 400 mg/kg, injected intravenously, corresponding to 200 mg/kg of acetaminophen) produced a significant antinociceptive effect in this test. This effect was at least partially inhibited by intrathecal (i.t.) pretreatment with the 5-HT(1B) (penbutolol), 5-HT(2A) (ketanserin), 5-HT(2C) (mesulergine) receptor antagonists, but not by the 5-HT(1A) (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride, WAY 100635) and 5-HT(3) (granisetron) receptor antagonists. This profile was very close to that obtained recently with 5-HT, which suggests an implication of 5-HT in the spinal antinociceptive effect of acetaminophen. These results, the lack of binding of acetaminophen to 5-HT receptors and the increase of central 5-HT levels induced by this drug suggest that acetaminophen-induced antinociception could be indirectly mediated by 5-HT.

Effects of rapid eye movement (REM) sleep deprivation on pain sensitivity in the rat.

The relationship between pain and sleep seems to be reciprocal: if pain may interrupt or disturb sleep, poor sleep can also influence pain perception. However the influence of sleep disturbances on pain sensitivity remain poorly investigated. The aim of this study was to assess the effect of REM sleep deprivation on the reaction of rats subjected to different noxious stimuli. In each experiment 16 Wistar male rats were randomly assigned to two groups: controls (n=8), and REM sleep deprived rats (n=8). REM sleep deprivation was elicited using the 'inverted flower pot' technique. Four different experiments were performed to assess the sensitivity to mechanical (vocalization threshold in paw pressure), thermal (tail withdrawal latency in hot water immersion), electrical (envelope of 2nd peep in tail shock test) and chemical (analgesic behavior in formalin test) noxious stimuli. All experiments were performed over a 5-day period with baseline (day 1, day 2) in a dry environment and REM sleep deprivation (day 3, day 4 and day 5) in a wet environment. Under wet conditions, vocalization threshold in the paw pressure test (-20%, P=0.005), and tail withdrawal latency in the hot water immersion test (-21%, P=0.006) were significantly lower, and the envelope of 2nd peep in the tail electrical shock was significantly greater (+78%, P=0.009), in REM sleep deprived rats compared to controls. However, under wet conditions the mean duration of nociceptive behaviors in the formalin test did not differ between the two groups. In conclusion, REM sleep deprivation induces a significant increase in the behavioral responses to noxious mechanical, thermal and electrical stimuli in rats.

The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects.

The aim of this study was to compare the effects of total sleep deprivation (TSD), rapid eye movement (REM) sleep and slow wave sleep (SWS) interruption and sleep recovery on mechanical and thermal pain sensitivity in healthy adults. Nine healthy male volunteers (age 26--43 years) were randomly assigned in this double blind and crossover study to undergo either REM sleep or SWS interruption. Periods of 6 consecutive laboratory nights separated by at least 2 weeks were designed as follows: N1 Adaptation night; N2 Baseline night; N3 Total sleep deprivation (40 h); N4 and N5 SWS or REM sleep interruption; N6 Recovery. Sleep was recorded and scored using standard methods. Tolerance thresholds to mechanical and thermal pain were assessed using an electronic pressure dolorimeter and a thermode operating on a Peltier principle. Relative to baseline levels, TSD decreased significantly mechanical pain thresholds (-8%). Both REM sleep and SWS interruption tended to decrease mechanical pain thresholds. Recovery sleep, after SWS interruption produced a significant increase in mechanical pain thresholds (+ 15%). Recovery sleep after REM sleep interruption did not significantly increase mechanical pain thresholds. No significant differences in thermal pain thresholds were detected between and within periods. In conclusion this experimental study in healthy adult volunteers has demonstrated an hyperalgesic effect related to 40 h TSD and an analgesic effect related to SWS recovery. The analgesic effect of SWS recovery is apparently greater than the analgesia induced by level I (World Health Organization) analgesic compounds in mechanical pain experiments in healthy volunteers.

Potentiation of the antinociceptive effect of clomipramine by a 5-ht(1A) antagonist in neuropathic pain in rats.

The benefit of antidepressant treatment in human neuropathic pain is now well documented, but the effect is limited and slow to appear. It has been demonstrated that the association of a 5-HT(1A) antagonist and a serotoninergic antidepressant reduced the delay of action and increases the thymoanaleptic effect of the drug. The purpose of this work was to evaluate the combination of an antidepressant and a 5-HT(1A) antagonist in animal models of chronic neuropathic pain. We studied the antinociceptive effect of the co-administration of clomipramine and a 5-HT(1A) antagonist (WAY 100,635) in a pain test applied in normal rats and in two models of neurogenic sustained pain (mononeuropathic and diabetic rats). The results show an increase in the antinociceptive effect of acutely injected clomipramine due to WAY 100,635 in these models, which is majored when the two drugs are repeatedly injected. The 5-HT(1A) antagonist reduced the delay of onset and increased the maximal antinociceptive effect of clomipramine. These new findings argue for using the combination of an antidepressant and a 5-HT(1A) antagonist in human neuropathic pain therapy.

Effect of intrathecal administration of serotonin in chronic pain models in rats.

The present study examined the effects of intrathecal (i.t.) administration of 5-hydroxytryptamine (5-HT; 0.1-100 microg) on mechanical hyperalgesia associated with neuropathic pain (chronic constriction of the sciatic nerve model and diabetic model) and inflammatory pain (carrageenan and polyarthritic models) in rats. Results demonstrated that the hyperalgesia observed in the mononeuropathic and diabetic rats was attenuated by 5-HT; the active dose, however, was 100- to 1000-fold higher than that required in normal rats, and was moderately effective. In the two experimental models of inflammatory pain, 5-HT was not markedly or similarly active. In the carrageenan model, 5-HT at the highest dose was only weakly effective whereas in the polyarthritic model it was inactive. Together, these results show that 5-HT has antinociceptive effects in several rat pain models, except in the model of diffuse pain (polyarthritic rats). Its antinociceptive effects in these models, however, are slight and differ from those observed in normal rats.

Age-related changes in nociception and effect of morphine in the Lou rat.

Little is known about how the ageing process affects pain sensitivity and a relevant animal model is therefore required. The effect of age on pain reactivity in animals has been investigated by several experimenters but the results are conflicting. Four groups of male and female Lou/C/Jall rats (4-29 months old) were used for our study. Four pain tests based on evaluation of reflex or more integrated behaviours after a thermal (tail immersion test) or mechanical (paw pressure test and von Frey test) stimulation were used. With mechanical stimulus, a significant decrease in the pain threshold across age was observed, females were more sensitive than males. This increase in nociceptive sensitivity to mechanical stimulation was more pronounced on integrated behaviours (struggle reaction) than on withdrawal reflex. An age-related increase in sensitivity was found on von Frey test. No effect on the latency of reflex induced by thermal stimulation was observed. In addition, a decrease in the spontaneous motor activity during exploration was observed across ageing; this effect was more marked for the females. The effect of morphine at doses of 1, 3 and 9 mg/kg (s.c.) decreased in intensity across ageing. These data demonstrate the need to use (1) various noxious stimuli because differences were observed in the modification of pain reactivity according to the nature of the stimulus; (2) various pain parameters and particularly integrated behaviours; (3) several age groups. In addition, Lou/C/Jall rat could be a useful model for studying of effect of age on pain.

Vocalization thresholds related to noxious paw pressure are decreased by paradoxical sleep deprivation and increased after sleep recovery in rat.

The aim of this study was to assess the effect of paradoxical sleep deprivation (PSD) and sleep recovery on the vocalization threshold in rats submitted to a mechanical noxious stimulus. Sixteen male Wistar rats were randomly assigned in two groups: controls (n=8), paradoxical sleep deprived rats (n=8). PSD was performed using the 'inverted flower pot' technique. Paw pressure test was used to assess the sensitivity to mechanical noxious stimulus (vocalization threshold). The experiment was divided into three periods: baseline (day 1, day 2), PSD (day 3, day 4, day 5) and recovery (day 6, day 7, day 8, day 9). After 48 and 72 h of PSD, the vocalization thresholds decreased significantly in comparison to the control rats (day 4: 245+/-21 vs. 303+/-20 g, P=0.05; day 5: 256+/-17 vs. 324+/-22 g, P=0.02). In PSD group, relative to controls, vocalization thresholds increased significantly after 48, 72, and 96 h of recovery sleep periods (day 7: 378+/-24 vs. 307+/-8 g P=0.01; day 8: 384+/-27 vs. 316+/-23 g, P=0.02; day 9: 395+/-24 vs. 328+/-15 g, P=0.02). Vocalization thresholds on day 6 were not significantly different in both groups (375+/-20 vs. 324+/-24 g, P=0.08). In conclusion, experimental PSD in rats induces a significant decrease in vocalization threshold to mechanical noxious stimulus, which is totally reversed during the sleep recovery period.

Pharmacological validation of an automated method of pain scoring in the formalin test in rats.

In 1997, we described a new automated method of scoring the pain behaviors in the formalin test. The algic behavior was automatically measured with the help of a video-analysis system. The time during which the animal grooms, licks, or bites itself was used as the parameter of pain. In the present study, we tested various analgesics to realize a pharmacological validation of the system. The effect of opiate analgesic (morphine, i.v.), nonsteroidal anti-inflammatory drugs (paracetamol, i.v., piroxicam, i.v., indomethacin, i.v.), antidepressant drugs (clomipramine, desipramine, nortryptyline, and paroxetine, i.p.), and serotonin (i.t.) were analyzed. A dose of 1.25 mg/kg of morphine induced a decrease in the scores of phases 1 and 2. Naloxone (0.25 mg/kg) reversed the effect of morphine (2.5 mg/kg). A 20-mg/kg dose of indomethacin induced a decrease in the second phase, and paracetamol induced a decrease in both phases (analgesic doses were 400 mg/kg and 200 mg/kg for first and second phases, respectively). Piroxicam had no effect on the pain scores. Clomipramine, desipramine, and paroxetine at a dose of 5 mg/kg induced a significant decrease in the second phase. Nortriptyline had no effect on the pain scores. A dose of 75 microg of serotonin induced a decrease in both phases 1 and 2. This study demonstrated that this system shows a good pharmacological sensitivity, although it is lower than that of manual assessment.

Evidence for a role for bulbospinal pathways in the spinal antinociceptive effect of systemically administered vapreotide in normal rats.

Numerous neurotransmitters are involved in nociceptive transmission or regulation. Several reports have shown the analgesic effects of somatostatin and its analogues. Somatostatin, when given intrathecally, markedly reduced pain in cancer patients. Somatostatin analogues that possess a longer half-life time are more convenient for therapeutic use. Vapreotide, a somatostatin analogue, was shown to induce a long-lasting antinociceptive effect in rats. We studied the site and the mechanism of action of vapreotide in rats using the paw pressure test. Intrathecal administration of vapreotide induced no antinociception. Systemically administered vapreotide-induced antinociception was inhibited by several intrathecal (i.t.) administered antagonists (yohimbine, naloxone and to a lesser degree tropisetron). These results show a lack of spinal effect and suggest a supraspinal site of action with an involvement of noradrenergic and to a lesser degree serotonergic bulbospinal pathways. In addition, spinal opioid receptors also seen to be involved.

Differential influence of two serotonin 5-HT3 receptor antagonists on spinal serotonin-induced analgesia in rats.

We tested the antinociceptive effect of intrathecal (i.t.) administration of 5-HT3 and the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), in rats submitted to a mechanical noxious stimulus and the influence of the 5-HT3 receptor selective antagonists, tropisetron and granisetron. Both 5-HT and mCPBG (0.01, 0.1, 1, 10, 20 micrograms/rat) produced a significant dose-dependent antinociception. The lowest active doses were 0.1 and 1 microgram for 5-HT and mCPBG, respectively. The effect, observed with 20 micrograms, was significantly lower with mCPBG (+33 +/- 6%) than with 5-HT (+63 +/- 7%). For 5-HT-induced antinociception, the minimal inhibitory doses were 0.001 micrograms/rat for tropisetron and 10 micrograms/rat for granisetron. In contrast, the same doses of the two antagonists (from 0.1 microgram/rat) similarly inhibited the effect of mCPBG. This study provides evidence that contrary to tropisetron, doses of granisetron able to inhibit the effect of a 5-HT3 receptor agonist failed to reduce that of 5-HT. This demonstrates a heterogeneity between 5-HT3 receptor antagonists and questions the true involvement of these receptors in spinal 5-HT-induced antinociception.

Magnesium deficiency induces an hyperalgesia reversed by the NMDA receptor antagonist MK801.

The aim of this study was to determine the changes of the nociceptive thresholds in response to an acute mechanical stimulus (paw pressure) in magnesium (Mg)-deficient rats, and the involvement of the NMDA receptor in these changes. Changes in vocalization thresholds was determined after 7 days of feeding with a Mg-depleted diet. Compared with the control group, Mg-deficient rats showed a significant decrease in the vocalization thresholds (-35.8 +/- 2.5%, p < 0.001) reflecting hyperalgesia. In Mg-deprived rats, three doses (0.06, 0.12 and 0.24 mg/kg s.c.) of dizocilpine (MK801), a non-competitive NMDA receptor antagonist, significantly reversed the hyperalgesia in a dose-dependent manner for at least 48 h. No effect of MK801 was observed in the control group. These data provide evidence that Mg deficiency could constitute a new model of hyperalgesia involving NMDA receptors.

Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytryptamine3 receptors: in vivo and in vitro evidence.

Rats (Sprague-Dawley), submitted to a mechanical noxious stimulus (paw pressure), were tested to determine 1) the antinociceptive effects of p.o. (200, 400 and 800 mg/kg), i.v. (50, 100, 200 and 300 mg/kg) and intrathecal (i.t.) (100 and 200 micrograms/rat) administrations of paracetamol; 2) the influence of i.t. administered tropisetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist (0.5, 1 or 10 micrograms/rat) on paracetamol-induced antinociception; 3) the influence of indomethacin (25 mg/kg s.c.), naloxone (10 micrograms/rat i.t.) and yohimbine (1 mg/kg i.v.) on the effect of paracetamol (200 mg/kg i.v.) to determine the involvement of prostaglandins, opioids and alpha-2 adrenoceptors. The displacement by paracetamol of radioligand binding to various receptors was also investigated. Paracetamol induced a significant antinociceptive effect after p.o., i.v. and i.t. administration. A total inhibition of the effect of paracetamol, administered p.o. or i.t., occurred at the dose of 0.5 microgram/rat of tropisetron, whereas 10 micrograms/rat of this antagonist was needed to totally inhibit the action of i.v. administered paracetamol. Indomethacin, naloxone and yohimbine failed to modify paracetamol antinociceptive action. In vitro studies failed to show any binding of paracetamol to 5-HT3 and several other receptors and to 5-HT uptake sites. It is concluded that paracetamol has a central antinociceptive effect, based on an indirect involvement of spinal 5-HT3 receptors.

Evidence of a central antinociceptive effect of paracetamol involving spinal 5HT3 receptors.

This study was carried out to determine both the effect of systemic paracetamol on the C-fibre evoked reflex activity, a test sensitive to centrally acting analgesic drugs, and the influence of an intrathecally administered 5HT3 receptor antagonist, tropisetron. Paracetamol (200, 300, 400 mg kg-1, i.v.) dose-dependently decreased (maximal effects -60 +/- 8%) the C-evoked responses for a duration of 90 min (for the lowest dose). This effect was totally suppressed by tropisetron (1 microgram, i.t.). These data confirm previous studies suggesting a central effect of this drug and demonstrate the involvement of a spinal 5HT3 mediated serotonergic mechanism.

Cardiovascular profile of oxodipine, a novel dihydropyridine calcium channel blocker, in anesthetized open-chest dogs: a comparison with nitrendipine.

The cardiovascular effects of oxodipine, a new dihydropyridine calcium channel blocker, were studied after i.v. administration to chloralose-anesthetized dogs, and compared with those of nitrendipine. Nitrendipine produced more marked decreases than oxodipine in both systolic and diastolic blood pressure and in total peripheral resistance. No significant modification of heart rate was observed. Oxodipine decreased cardiac contractility, whereas nitrendipine increased it. This difference originated in reflex modifications, since both drugs, administered at doses of 30 and 60 micrograms/kg, decreased cardiac contractility during studies performed after cardiac autonomic blockade. Under these conditions, nitrendipine decreased heart rate, whereas oxodipine had no effect. The two drugs showed comparable effects on coronary and femoral vascular resistance. However, oxodipine caused a very marked persistent decrease of vertebral vascular resistance. On this local circulation, nitrendipine had a weak effect. The results from the present study indicate that oxodipine predominantly increases vertebral blood flow with a concomitant hypertension which is more moderate than after nitrendipine.