J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine.

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats.

Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic.

The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons.

BACKGROUND: Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. METHODS: Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. RESULTS: BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons. CONCLUSION: The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain.

The putative OP(4) antagonist, [Nphe(1)]nociceptin(1-13)NH(2), prevents the effects of nociceptin in neuropathic rats.

Nociceptin or orphanin FQ (N/OFQ) is the natural ligand of the opioid receptor-like 1 receptor (ORL-1), which has been also classified as the fourth member of the opioid family of receptors and named OP(4). Elucidation of the biological role of N/OFQ has been hampered by the lack of compounds that selectively block the OP(4) receptor. Recently, a N/OFQ derivative, [Nphe(1)]N/OFQ(1-13)NH(2), has been found to possess OP(4) antagonistic properties both in vitro and in vivo models. We investigated its spinal effect in the chronic constriction injury of the sciatic nerve in the rat, a model relevant to neuropathic pain in humans. Intrathecal (i.t.) administration of N/OFQ (0.2--20 nmoles) dose-dependently reversed mechanical allodynic-like behavior, while [Nphe(1)]N/OFQ(1-13)NH(2) (20--120 nmoles, i.t.) was ineffective on its own. [Nphe(1)]N/OFQ(1-13)NH(2) (60--120 nmoles, i.t.) antagonized N/OFQ (about 80% of reduction) but did not modify the activity of morphine (20 nmoles, i.t.). These results further support, for the first time in a chronic model of pain, the specific antagonistic profile of [Nphe(1)]N/OFQ(1-13)NH(2)vs the OP(4) receptor. This pseudopeptide is an interesting pharmacological tool to better clarify the role of N/OFQ in pathophysiology.

Nociceptin attenuates opioid and gamma-aminobutyric acid(B) receptor-mediated analgesia in the mouse tail-flick assay.

Nociceptin (NC) and the opioid receptor like-1 receptors are widely distributed in areas of the neuraxis that are part of the descending modulatory pain system. We used the tail-flick assay in mice to assess the interaction between NC and other analgesic compounds acting on different areas of the descending pathway. Given by intracerebroventricular injection, NC induced hyperalgesia at 10 nmol (39% of reduction vs. control group). The same dose of NC reversed analgesia induced by distinct classes of analgesia-producing compounds such as morphine, dynorphin A or baclofen. NC caused a reduction of their antinociceptive effects: 61, 41 and 27%, respectively. Thus, NC at the supraspinal level appears to interact with both opioid and gamma-aminobutyric acid(B) systems producing anti-analgesic effects probably through the descending pathway for pain control.

Nociceptin and the ORL-1 ligand [Phe1psi (CH2-NH)Gly2]nociceptin(1-13)NH2 exert anti-opioid effects in the Freund's adjuvant-induced arthritic rat model of chronic pain.

1 Stimulation of the opioid receptor-like1 (ORL-1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated. 2 The present study was undertaken to assess the action of NC in the Freund's adjuvant-induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL-1 ligand, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), were also studied alone or in association with morphine. 3 NC (1 - 30 nmol, i. c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (-4.5+/-0.9 vs -0.7+/-0.8 s of vehicle-treated animals). [F/G]NC(1-13)NH2 (0.01 - 10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (-3.3+/-0.6 vs -0.3+/-0.5 s of vehicle-treated animals; 10 nmol). 4 Both NC (0.01 - 10 nmol, i.c.v. ) and [F/G]NC(1-13)NH2 (0.01 - 1 nmol, i.c.v), 30 min after morphine (3 mg kg-1, s.c.) induced an immediate and short-lived reversal of morphine effects (2.6+/-0.3 vs 10.4+/-1.0 and 1.2+/-1.5 vs 9.3+/-1.1 s of morphine alone, respectively), therefore displaying anti-opioid activity. 5 In the Freund's adjuvant-induced rat model of arthritis, both NC and [F/G]NC(1-13)NH2 act as anti-opioid peptides. Furthermore, NCNH2 and [F/G]NC(1-13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL-1 antagonist are necessary to better understand the role of NC in pain mechanisms.

Pseudotumor cerebri. Lumboperitoneal shunt in long lasting cases.

The Authors report three cases of pseudotumor cerebri with noteworthy visual defect. Lumboperitoneal shunt enables good recovery where there was no atrophy of the optic nerve and demonstrated its usefulness also in serious situations.

[Synovial lumbar cyst]. / Cisti sinoviale lombare.

The Authors report a case of low back pain with sciatica due to a synovial cyst of the interapophyseal joint of the lumbar spine. The diagnosis was made by CT and MRI. A review of the literature confirms the relative rarity of their lesion at the lumbar level and the necessity of radical surgery, best achieved with microsurgical technique. The Authors emphasize the importance of accurate diagnosis before surgery.

[Cerebral tuberculoma. Clinical case]. / Tubercoloma cerebrale. Caso clinico.

The authors report of a patients operated for a double encephalic mass in the left posterior parietal region. This lesion resulted a tubercoloma at a later investigation. This pathology is relatively common in underdeveloped countries, declining in western countries. The authors emphasize the need of a careful evaluation in searching tuberculous infection in presence of encephalic granulomatous masses.

[Extradural hematoma in the posterior cranial fossa. Experience with 4 cases]. / L'ematoma extradurale in fossa cranica posteriore. Esperienza su 4 casi.

The authors report their experience on treatment of posterior fossa epidural hematoma. They emphasize the role of a quick diagnosis, in times past often difficult, novadey easier with the aid of the CT.

Why may epsilon-aminocaproic acid (EACA) induce myopathy in man? Report of a case and literature review.

A case of necrotizing myopathy due to a short epsilon-aminocaproic acid (EACA) treatment in a 72 year-old patient with subarachnoid haemorrhage (SAH) is described. Pathogenetic hypotheses are discussed.

[Detection of Salmonella carriers among the dogs of the province of Ferrara. Isolations in 1 year and antibiotic-resistance]. / Ricerca di portatori di Salmonelle fra i cani in provincia di Ferrara. Isolamenti in un anno e antibiotico-resistenza.

When fecal samples were examined from 2.138 dogs, 166 (7.16 per cent) yelded Salmonellae of 30 different serotypes. The most frequent serotypes found were S. saint paul, S. typhimurium, S. hadar, S. haifa, S. brandenburg, S. london, S. agona, S. enteritidis, A. meleagridis, S. bredeney, S. infantis, S. panama, S. reading. The antibiotic susceptibility tests against 11 drugs showed resistance to sulphonamides.

[Microbiological pollution of the environment due to breeding. I. Enterobacteriaceae due to cattle breeding]. / Sull'inquinamento microbiologico dell'ambiente da parte degli allevamenti. Nota I: Enterobacteriaceae da allevamenti bovini.

Enterobacteriaceae from faeces of cattle belonging to four cattle farms situated in the Ferrara district were investigated. At the same time, investigation was made of effluent sewage and recipient wells (upstream and downstream). The cattle (of the Italian Frisona breed) resulted uncontaminated by Salmonellae, but proved to be very susceptible to Arizona, Citrobacter, Shigella and S. gallinarum-pullorum infections, coming from the environment. Predominant species in faeces were as follows: Proteus, Klebsiella, Enterbacter and coliforms. One farm proved to be heavily polluted by Edwardsiella tarda. Yersinia enterocolitica strains were also isolated from faeces and sewage.