PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice.

Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.

1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice.

Neuropathic pain is a devastating neurological disease that seriously affects quality of life in patients. The mechanisms leading to the development and maintenance of neuropathic pain are still poorly understood. However, recent evidence points towards a role of spinal microglia in the modulation of neuronal mechanisms. In this context, cannabinoids are thought to modulate synaptic plasticity as well as glial functions. Here, we have investigated the effect of chronic treatment with a selective agonist of cannabinoid type 2 receptor (CB2), 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3 carboxamide (NESS400), on pain thresholds in the spared nerve injury (SNI) model in the mouse and on the distribution and activation of spinal microglia. Repeated treatment with NESS400 (4 mg/kg) significantly alleviated neuropathic mechanical allodynia and thermal hyperalgesia. In the dorsal horn (L4-L6) of neuropathic mice microglia activation (quantification of the length of microglial processes) and astrocytosis were associated with CB2 receptor over-expression on both cell types. Treatment with NESS400 significantly reduced the number of hypertrophic microglia while leaving microglial cell number unaffected and reduced astrogliosis. Moreover, prolonged administration of NESS400 reduced mRNA expression of pro-inflammatory markers and enhanced anti-inflammatory marker gene expression in dorsal horn extracts. In conclusion, we show that selective CB2 receptor stimulation prevents thermal hyperalgesia, alleviates mechanical allodynia and facilitates the proliferation of anti-inflammatory microglial phenotype in the ipsilateral dorsal horn of the spinal cord in SNI mice.

Sufentanil-propofol vs remifentanil-propofol during total intravenous anesthesia for neurosurgery. A multicentre study.

BACKGROUND: In a randomised, prospective multi-centre study, we compared the intraoperative and postoperative effects of two opioids: sufentanil and remifentanil, in combination with propofol in two groups of patients undergoing neurosurgery. METHODS: After Local Ethics Committee approval and informed consent obtaining, 69 patients undergoing neurosurgery for supratentorial tumours, between 18 and 75 years of age were randomised to receive either sufentanil or remifentanil in combination with propofol. Intraoperative and postoperative haemodynamic variables, recovery times (time to eye opening and to extubation), the incidence of postoperative respiratory depression, pain, nausea and vomiting were also evaluated. The Short Orientation-Memory-Concentration Test was used to evaluate cognitive function at 15, 45 and 180 min after emergence from anesthesia. RESULTS: There were no significant differences between the groups in the duration of surgery and anesthesia, mean arterial pressure, heart rate, time to eye opening or extubation. The incidence of vomiting, respiratory depression and shivering was similar in both groups. Postoperative pain requiring supplemental analgesics was significantly lower in the sufentanil group (P<0.05). Although there were no significant differences between the groups in postoperative behavioural examinations by Rancho Los Amigos Test, patients anesthetised with sufentanil had significantly better Short Orientation-Memory-Concentration Test values at 15 and 180 min postoperatively (P<0.05). CONCLUSION. We conclude that remifentanil and sufentanil are suitable adjunct to propofol for total intravenous anesthesia (TIVA). Patients receiving sufentanil have reduced analgesic requirements and better cognitive function postoperatively than those who received remifentanil.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on inflammatory and neuropathic pain in mice.

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat.

This study was undertaken to analyze the involvement of periaqueductal gray (PAG) cannabinoid or group I metabotropic glutamate receptors in the formalin-induced changes on the rostral ventromedial medulla (RVM) ON- and OFF-cells activities. S.c. injection of formalin into the hind paw produced a transient decrease (4-6 min) followed by a longer increase (25-35 min) in tail flick latencies. Formalin also increased basal activity in RVM ON-cells (42+/-7%) and decreased it in OFF-cells (35+/-4%). Intra-PAG microinjection of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2 nmol/rat), a cannabinoid receptor agonist, prevented the formalin-induced changes in RVM cell activities. Higher dosages of WIN 55,212-2 (4-8 nmol/rat) increased the tail flick latencies, delayed the tail flick-related onset to ON-cell burst, and decreased the duration of OFF-cell pause. Furthermore, WIN 55,212-2 at a dosage of 8 nmol/rat decreased RVM ON-cell (57+/-7%) and increased OFF-cell ongoing activities (26+/-4%). These effects were prevented by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide SR141716A, (1 pmol/rat), a CB1 cannabinoid receptor antagonist, or by 2-methyl-6-(phenylethynyl)pyridine (MPEP 20 nmol/rat), a selective mGlu5 glutamate receptor antagonist. T7-(hydroxyimino) cyclopropa[b]chromen-1alpha-carboxylate ethyl ester (CPCOOE/50 nmol/rat) and (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385, 20 nmol/rat), selective mGlu1 glutamate receptor antagonists, were ineffective in preventing the WIN-induced effects. This study suggests that s.c. injection of formalin modifies RVM neuronal activities and this effect is prevented by PAG cannabinoid receptor stimulation. Moreover, the physiological stimulation of PAG mGlu5, but not mGlu1 glutamate receptors, seems to be required for the cannabinoid-mediated effect.

Antibiotic drug prescription in respiratory tract infections: a pharmacoepidemiological survey among general practitioners in a region of Italy.

Data concerning patients undergoing antibiotic treatment for upper (URTI) or lower (LRTI) respiratory tract infections were collected from 23 General Practitioners (GPs) in the Campania Region of Italy from November 15, 1997 to March 15, 1998. The objectives of the study were: a) to assess the occurrence of URTIs and LRTIs; b) to document the factors that influence GPs' choice of therapy; c) to correlate antibiotic choice with duration and outcome of treatment; d) to assess the incidence of unwanted effects. 2198 questionnaires were collected. Patients were +/-43.9 of age. URTIs were diagnosed in 65.4% and 34.6% LRTIs. The mean duration of antibiotic treatment was 4.5 days in URTIs and 5.6 days in LRTIs. The choice of antibiotic treatment was influenced by clinical assessment of infections (67.1%). The most commonly used antibiotic categories in URTIs were macrolides (39.3%), penicillins (27.4%) and cephalosporins (23.8%) whereas for LRTIs mainly cephalosporins (63.8%), penicillins (9.2%) and fluoroquinolones (7.4%) were used. Adverse events were experienced by 3.9% of patients.

Role of hyperbaric oxygen exposure in reduction of lipid peroxidation and in multiple organ failure induced by zymosan administration in the rat.

The aim of the present study was to evaluate the effects of hyperbaric oxygen (HBO) therapy on multiple organ failure induced by zymosan. Administration of zymosan (500 mg/kg) in the rat induced neutrophil infiltration in the lung, liver, and intestine as evaluated by increase in myeloperoxidase (MPO) activity. Therefore, lipid peroxidation was significantly increased in zymosan-treated rats. This inflammatory process coincided with the damage of lung, liver, and small intestine. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the lung, liver, and small intestine of zymosan-shocked rats. HBO (2 absolute Atmosphere) exposure attenuates the increase in the tissue levels of MPO and malondialdehyde (MDA) caused by zymosan in the lung, liver, and intestine. In addition, HBO (2 absolute Atmosphere) was effective in preventing the development of lung, liver, and intestine injury. Taken together, the present results demonstrate that HBO may also be an efficacious treatment in multiple organ failure induced by zymosan.

Effects of hyperbaric oxygen exposure on a zymosan-induced shock model.

OBJECTIVE: To evaluate the effects of hyperbaric oxygen (HBO) therapy on zymosan-induced shock in rats. Zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation by causing the production of various cytokines and pro-inflammatory mediators. The administration of zymosan to rats represents a new experimental shock model by inducing acute peritonitis, severe hypotension, and signs of systemic illness. However, it has been recently proposed that the zymosan-induced shock, like septic shock, may be mediated by overproduction of nitric oxide. DESIGN: Experimental study. SETTING: Institute of Pharmacology and Toxicology, 2nd University of Naples, Naples, Italy. SUBJECTS: Male rats were treated with zymosan (500 mg/kg) by intraperitoneal route, with HBO (2 Absolute Atmosphere) or with zymosan and HBO (2 Absolute Atmosphere). MEASUREMENTS AND MAIN RESULTS: Peritoneal exudate, plasma, and peritoneal nitric oxide metabolites (NOx) and zymosan determined a time-dependent increase in peritoneal and plasma NOx concentrations, and peritoneal leukocytes were determined. Moreover, symptomatology was observed. The administration of zymosan caused the appearance of a severe illness in the rats characterized by ruffled fur, lethargy, conjunctivitis, diarrhea, and a significant loss of body weight. All zymosan-treated rats developed an acute peritonitis, producing turbid exudate. Zymosan determined a time-dependent increase in peritoneal, plasma NOx, and tumor necrosis factor (TNF)-alpha concentrations. Morbidity of zymosan shocked rats has been attenuated and no mortality was observed by treatment with HBO. These findings were associated with a significant reduction either of peritoneal leukocytes and exudate, or plasma and peritoneal NOx concentrations. Moreover, TNF-alpha levels were significantly reduced in animals shocked by zymosan and treated with HBO.

Effects of hyperbaric oxygen exposure on non-adrenergic non-cholinergic responses of rat trachea.

The effects of prolonged (20 day) hyperbaric exposure (HBO) to oxygen on non adrenergic non cholinergic (NANC) contractile and relaxant responses of rat trachea were examined. The electrical field stimulation (EFS) of rat tracheal rings was performed at 30 Hz and contractile and relaxant responses were assessed in the absence or in the presence of pretreatment with L-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase, and L-Arginine (L-ARG), a precursor of NO synthesis, plus L-NAME. Our data demonstrated that L-NAME significantly (p < 0.05) enhanced the contractile responses induced by EFS (controls 30.6 +/- 0.99%; L-NAME 76.07 +/- 2.00%) and statistically (p < 0.05) reduced the relaxant component of EFS (controls 31.10 +/- 0.46; L-NAME 15.00 +/- 0.12); these effects were reversed when tissues were pretreated with L-ARG plus L-NAME, suggesting that NO plays a modulatory role in cholinergic neurotransmission and participates in EFS relaxant responses. Moreover, prolonged HBO exposure (20 days) at 202.6 and 303.9 kPa did not modify the contractile or relaxant responses induced by EFS, nor modify the L-NAME or L-ARG effects on EFS responses.

[Total intravenous anesthesia in neurosurgical patients]. / Anestesia totalmente endovenosa in pazienti neurochirurgici.

The authors present an anesthesiologic technique, consisting of the use of propofol + fentanyl + O2. The main advantages, described in 82 neurosurgically treated patients, are the following: moderate decrease both of ICP and MAP, absence of frequency, modifications rapid recovery both of consciousness and of motility, which allows a preliminary valuation of neurological status.

[Urapidil: hypotension induced in neuroanesthesia]. / Urapidil: ipotensione indotta in neuroanestesia.

The authors report their experience on the use of urapidil in 31 patients, submitted to neurosurgical procedures. Urapidil, administered both in the inductive (0.7-1 mg/kg) and in preoperative phases (0.6-0.8 mg/kg/h), produced a MAP decrease of about 25% without significant variations in cardiac frequency or of other monitored parameters.

Effects of the intraperitoneal administration of diazepam on rat serum lipoproteins separated by polyacrylamide gel electrophoresis.

In normolipidaemic young rats the intraperitoneal administration of diazepam (10 mg/kg) induced a marked fall of the total serum lipids and total cholesterol. A dose of 5 mg/kg brought about an increase of HDL2 lipoprotein fraction and an elevation of the HDL2/HDL2.HDL3 ratio. Margarine administration elicited a significant augmentation of the total serum lipids and a reduction of the HDL2/HDL2.HDL3 ratio. The intraperitoneal injection of diazepam in margarine-treated rats brought about a decrease of total serum lipids and total cholesterol, (when compared to the margarine values), an obvious elevation of the HDL2 fraction and of HDL2/HDL2.HDL3 ratio. The LDL1 (beta) fraction was decreased. These data confirm our earlier findings which show that diazepam improves the HDL cholesterol/total cholesterol ratio.

Amides of benzonorbornen-2-endo-amine with local anesthetic and other activities.

The synthesis of a series of amides derived from benzonorbornen-2-endo-amine is described. Some compounds showed a remarkable infiltration anesthesia in mice and a moderate hypotensive activity in rats. Antiarrhythmic activity in mice is also reported.