Limbic seizures increase pronociceptin mRNA levels in the thalamic reticular nucleus

We studied pronociceptin gene expression following limbic seizures. Northern blot analysis revealed increased pronociceptin mRNA levels in the thalamus (but not in the hippocampus) 3-24 h after kainate administration, with maximal effect (2-fold increase over basal levels) reached at 6 h. No variation in pronociceptin mRNA levels was observed 1-6 h after a stimulus-evoked kindled seizure. Carrageenan failed to affect pronociceptin gene expression in the thalamus, indicating that pain and/or acute stress do not account for kainate effects. In situ hybridization revealed that kainate evokes a dramatic (4-fold) increase in pronociceptin mRNA levels over the thalamic reticular nucleus. Kindled seizures evoked only a small, non-significant increase in pronociceptin gene expression over the dentate gyrus of the hippocampus.     

The effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain

The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(-)-2-(3 furylmethyl)-normetazocine] (MR 2266), a kappa-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. The values, expressed in pmol/g tissue, were: control = 2.83 +/- 0.20; paracetamol (100) = 2.60 +/- 0.23; morphine (3) = 2.73 +/- 0.24; paracetamol + morphine = 1.34 + 0.16 (P < 0.05). The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through kappa-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.     

The effect of paracetamol on nociception and dynorphin A levels in the rat brain

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.     

Antinociceptive profile of intracerebroventricular salmon calcitonin and calcitonin gene-related peptide in the mouse formalin test

The effects of intracerebroventricularly administered salmon calcitonin (sCT) and calcitonin gene-related peptide (CGRP) on the behavioural response of the mouse to formalin injections were investigated. Mice lick their hindpaws for 5 min after formalin injections, then stop, and resume intensive licking for another 10 min beginning 20 min after the injections. Both peptides reduced the nociceptive response in the two phases of the test (0-5 and 20-30 min after formalin injection). Antinociceptive A50 values were 3.3 micrograms/mouse and 4.7 micrograms/mouse respectively in the first phase for sCT and CGRP. The effects of sCT and CGRP appeared to be dose-dependent in the first phase. Since in the second phase sCT appeared more effective and CGRP gave a bell-shaped curve, possible differences in the mechanisms of action of the peptides in the two response intervals of the test are suggested.     

Protection by opioids against gastric lesions caused by necrotizing agents

The synthetic opioid met-enkephalin analog [D-Ala2, MePhe4, Met(0)5ol] enkephalin (DAMME) and the opiate morphine injected intraperitoneally to rats at doses of 0.5-2 and 5-20 mg/kg, respectively, showed a protective effect on gastric damage induced by oral administration of necrotizing agents (0.6 N HCl or 0.2 N NaOH solutions, 1 ml/rat). The protection was prevented by naltrexone (10 mg/kg s.c.), an opioid antagonist with long-lasting activity. Histological sections of mucosal samples from animals pretreated with morphine (10 mg/kg i.p.) and DAMME (1 mg/kg i.p.) showed less alteration of the columnar epithelium, with a normal glandular structure, than untreated rats. A mediation of prostaglandins is suggested, since indomethacin (10 mg/kg s.c.) significantly reduced the protective effects of opioids.     

Antinociceptive activity of salmon calcitonin injected intrathecally in the rat

Salmon calcitonin injected intrathecally in unanesthetized rats produced long-lasting, dose-dependent elevations of nociceptive threshold as measured in the hot plate test. This antinociceptive action was nonopiate in nature as it was uninfluenced by the narcotic antagonists naloxone and MR 1452; moreover, the peptide was still able to raise the nociceptive threshold in morphine-tolerant rats. It is suggested that the spinal cord may represent one of the sites of action for calcitonin-induced antinociception.     

Effects of prolonged treatment with the opiate tramadol on prodynorphin gene expression in rat CNS

A low abuse liability is reported for tramadol, an analgesic drug centrally acting through either opioid or nonopioid mechanisms. In this paper, we evaluated the effects of the repeated administration (7 d) of different doses of tramadol (10, 20, and 80 mg/kg, intraperitoneally) on the opioid precursor prodynorphin biosynthesis, in comparison with morphine (10 mg/kg, intraperitoneally), in the rat central nervous system (CNS). Northern analysis showed that morphine and tramadol produced different effects. While morphine caused a down-regulation of prodynorphin mRNA levels in all investigated areas (hypothalamus, hippocampus, and striatum), tramadol did not cause any significant change in the striatum, and did not decrease prodynorphin biosynthesis in the hypothalamus and in the hippocampus, at nontoxic doses (10 and 20 mg/kg). The highest dose of tramadol (80 mg/kg) decreased prodynorphin mRNA levels in the hypothalamus and the hippocampus but not in the striatum. These data give some information on tramadol effects at molecular level in the CNS. They indicate that the alterations of prodynorphin gene expression caused by tramadol and morphine show a different pattern that may be related to the different abuse potential of the two analgesic drugs.     

Phimosis and topical steroids: new clinical findings

Phimosis has been defined as unretractable foreskin without adherences and/or a circular band of tight prepuce preventing full retraction. The aim of this study is to evaluate the efficacy (response rate) of topical steroids for the treatment of tight phimosis at different age stages. After using the same medication with different dosage schemes, a retrospective analysis was carried out to assess the efficacy of topical steroids in the treatment of tight phimosis. Patients were divided into three groups: group A (betamethasone scheme A), group B (betamethasone scheme B) and group C (control group). Remission of phimosis, with a complete exposure and without a narrowing behind the glans, was considered a complete response to treatment. The outcomes were then related to dosage scheme and patient’s age. The dosage for group A was more effective than the dosage for groups B and C (control group). Phimosis resolved in 90% (group A), 72% (group B) and 56% (group C) of cases. A successful treatment was closely related to the age of patients at the beginning of steroid application. The results showed that treatment with topical steroids, which in general gives good results, proved to be much more successful in patients aged between 4 and 8 years, suggesting the efficacy of an early beginning of the treatment.