1,721,296 research outputs found
Methamphetamine alters prodynorphin gene expression and dynorphin A levels in rat hypothalamus
No full textChronic administration of morphine or cocaine affects opioid gene expression. To better understand the possible existence of common neuronal pathways shared by different classes of drugs of abuse, we studied the effects of methamphetamine on the gene expression of the opioid precursor prodynorphin and on the levels of peptide dynorphin A in the rat brain. Acute (6 mg/kg, intraperitoneally, i.p.) and chronic (6 mg/kg, i.p. for 15 days) methamphetamine markedly raised prodynorphin mRNA levels in the hypothalamus, whereas no effect was observed in the hippocampus. Dynorphin A levels increased after chronic treatment in the hypothalamus and in the striatum, whereas no significant changes were detected after acute treatment. These results indicate that methamphetamine affects prodynorphin gene expression in the hypothalamus, which may be an important site (also for its relevant neuroendocrine correlates) for opioidergic mechanisms activated by addictive drugs. Copyright (C) 1999 Elsevier Science B.V
Involvement of the Neuropeptide Nociceptin/Orphanin FQ in Kainate Seizures
No full textThe neuropeptide nociceptin/orphanin FQ (N/OFQ) has been shown to modulate neuronal excitability and neurotransmitter release. Previous studies indicate that the mRNA levels for the N/OFQ precursor (proN/OFQ) are increased after seizures. However, it is unclear whether N/OFQ plays a role in seizure expression. Therefore, (1) we analyzed proN/OFQ mRNA levels and NOP (the N/OFQ receptor) mRNA levels and receptor density in the kainate model of epilepsy, using Northern blot analysis, in situ hybridization, and receptor binding assay, and (2) we examined susceptibility to kainate seizure in mice treated with 1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-benzimidazol-2-one (J-113397), a selective NOP receptor antagonist, and in proN/OFQ knock-out mice. After kainate administration, increased proN/OFQ gene expression was observed in the reticular nucleus of the thalamus and in the medial nucleus of the amygdala. In contrast, NOP mRNA levels and receptor density decreased in the amygdala, hippocampus, thalamus, and cortex. Mice treated with the NOP receptor antagonist J-113397 displayed reduced susceptibility to kainate-induced seizures (i.e., significant reduction of behavioral seizure scores). N/OFQ knock-out mice were less susceptible to kainate seizures compared with their wild-type littermates, in that lethality was reduced, latency to generalized seizure onset was prolonged, and behavioral seizure scores decreased. Intracerebroventricular administration of N/OFQ prevented reduced susceptibility to kainate seizures in N/OFQ knock-out mice. These data indicate that acute limbic seizures are associated with increased N/OFQ release in selected areas, causing downregulation of NOP receptors and activation of N/OFQ biosynthesis, and support the notion that the N/OFQ-NOP system plays a facilitatory role in kainate seizure expression
Fentanyl citrate sublingual formulation (Vellofent®) for quick BTcP hindering
No full textThe management of cancer pain presents manifold challenges: Even though background pain is adequately controlled, patients frequently experience episodes of acute pain exacerbation known as breakthrough cancer pain (BTcP). The characteristics of BTcP are a rapid onset, a short duration, and a severe intensity. An innovative sublingual fentanyl citrate formulation (Vellofent®) has been developed to target BTcP. The new formulation allows to increase the solubility of fentanyl and to provide optimal oromucosal conditions for rapid drug absorption, thus featuring a shorter time to onset of pain relief (from 6 minutes post-administration)
The therapeutic potential of novel kappa opioid receptor-based treatments
No full textSimilarly to the μ opioid receptor, kappa opioid receptor (KOR), is present either in the central nervous system and peripherally. In the last years several molecules, able to interact with KOR, have been the focus of basic research for their therapeutic potential in the field of chronic pain, as well as in depression, autoimmune disorders and neurological diseases. Topic The role of KOR system and the consequent clinical effects derived by its activation or inhibition are discussed. Their potential therapeutic utilization in conditions of stress and drug relapse, besides chronic pain, is here presented, including the possible use of KOR-agonists in drug addiction. Moreover, the potential role of KOR-antagonists, KOR agonist-antagonists, and peripheral KOR agonists is proposed
Alghedon Fentanyl Transdermal System
No full textThe efficacy of transdermal fentanyl for cancer pain and chronic non-cancer pain (chronic lower back pain, rheumatoid arthritis, osteoarthritis, neuropathic pain) is well established. Several formulations of fentanyl transdermal systems have been developed to improve the drug delivery and prevent misuse of the active principle. The addition of a rate controlling membrane to the matrix system represented an important advance. The design and functional features of Alghedon patch are compared with other approved generic fentanyl transdermal systems, emphasizing the distinctiveness of Alghedon patch. Alghedon patch has no liquid component in the finished product, therefore no leakage of active ingredient from the system can occur. A rate-controlling membrane provides controlled release of the active substance from the matrix reservoir, ensuring that fentanyl delivery and entry into the microcirculation is not solely controlled by the skin's permeability to this active substance. Alghedon patch contains part of the drug (approximately 15%) in the skin-contact adhesive: This innovative solution allows to overcome a typical drawback of transdermal patches, i.e. The long lag-Time before the drug appears in plasma after the first administration, and provides rapid analgesia during the first hours of administration. Alghedon Fentanyl Transdermal System employs materials commonly used in other transdermal applications and having established safety profiles. For each strength level, the fentanyl content-and, thus, the resulting residual fentanyl remaining in the patch after use-is at the lowest end of the range used in commercially available fentanyl patches, minimizing the potential for abuse and misuse
Distinguishable effects of intrathecal dynorphins, somatostatin, neurotensin and s-calcitonin on nociception and motor function in the rat
No full textWe determined the effects on nociceptive threshold and motor function of dynorphin-gene products, dynorphin A-(1-32) (DYN A-(1-32), DYN A-(1-8), DYN B and DYN B-29 and the non-opioid peptides somatostatin, neurotensin and salmon calcitonin (s-CT) after intrathecal administration in the rat. DYN A-(1-32) (25 nmol) produced maximal elevation of tail-flick latency accompanied by severe hind limb paralysis and tail flaccidity lasting 6 h and still present at 24 h in several animals. Antinociception evaluated by the vocalization test wore off within 2 h. A lower dose of the peptide (6.25 nmol) did not alter the tail-flick reflex and motor function but significantly elevated the vocalization threshold. The other dynorphins showed weaker, short-lasting activity on the nociceptive threshold, the order of potency being as follows: DYN B-29 > DYN B > DYN A-(1-8). On the other hand, at the high doses DYN B (100 nmol) and DYN B-29 (50 and 100 nmol) caused moderately severe hind limb paralysis whereas DYN A-(1-8) did not cause any motor impairment up to the dose of 100 nmol. MR 1452, a relatively preferential antagonist of the κ opioid receptor, prevented both the antinociceptive and motor effects of dynorphins. Intrathecal somatostatin (25 nmol) had a profile of activity superimposable on that of DYN A-(1-32): long-lasting (up to 24 h) elevation of tail-flick latency with hind limb paralysis and a shorter (4 h) elevation of the vocalization threshold. MR 1452 did not modify these effects. Intrathecal neurotensin (25 nmol) and s-CT (0.5 nmol) did not alter tail-flick latency or vocalization threshold. However, adopting the hot plate as the analgesimetric test, both peptides elevated the time of hind paw licking, taken as an index of nociception. No signs of motor dysfunction were observed at the doses employed. © 1988
Treatment with the neurotoxic Aβ (25-35) peptide modulates the expression of neuroprotective factors Pin1, Sirtuin 1, and brain-derived neurotrophic factor in SH-SY5Y human neuroblastoma cells
Full text linkThe deposition of Amyloid β peptide plaques is a pathological hallmark of Alzheimer's disease (AD). The Aβ (25-35) peptide is regarded as the toxic fragment of full-length Aβ (1-42). The mechanism of its toxicity is not completely understood, along with its contribution to AD pathological processes. The aim of this study was to investigate the effect of the neurotoxic Aβ (25-35) peptide on the expression of the neuroprotective factors Pin1, Sirtuin1, and Bdnf in human neuroblastoma cells. Levels of Pin1, Sirtuin 1, and Bdnf were compared by real-time PCR and Western blotting in SH-SY5Y cells treated with Aβ (25-35) or administration vehicle. The level of Pin1 gene and protein expression was significantly decreased in cells exposed to 25μM Aβ (25-35) compared to vehicle-treated controls. Similarly, Sirtuin1 expression was significantly reduced by Aβ (25-35) exposure. In contrast, both Bdnf mRNA and protein levels were significantly increased by Aβ (25-35) treatment, suggesting the activation of a compensatory response to the insult. Both Pin1 and Sirtuin 1 exert a protective role by reducing the probability of plaque deposition, since they promote amyloid precursor protein processing through non-amyloidogenic pathways. The present results show that Aβ (25-35) peptide reduced the production of these neuroprotective proteins, thus further increasing Aβ generation
The k-opioid receptor agonist U-69593 prevents cocaine-induced DARPP-32 phosphorylation at Thr34 in the rat brain
No full textDARPP-32 (dopamine- and cAMP-regulated phosphoprotein) is a potent endogenous inhibitor of protein phosphatase-1, which plays an important role in dopaminergic transmission. A large body of evidence supports the key role of DARPP-32-dependent signalling in mediating the actions of multiple drugs of abuse, including cocaine, which, when acutely administered, increases the Thr34 phosphorylation of DARPP-32 in the striatal and cortical areas. In this study, we have examined the contribution of the kappa-opioid system to the regulation of DARPP-32 phosphorylation at Thr34, following acute cocaine administration, in selected rat brain areas.
Results showed that a single injection of cocaine induces a significant increase in DARPP-32 phosphorylation at Thr34 in the hippocampus, caudate putamen and prefrontal cortex. In addition, pretreatment with the kappa opioid receptor agonist U-69593 prevented cocaine effects in all the investigated areas. These data could be considered consistent with the ability of kappa opioid agonists to attenuate many behavioural effects of cocaine, and support the hypothesis of the potential usefulness of these drugs as functional antagonists of cocaine
Epigenetic mechanisms of rapid-acting antidepressants
No full textBackground: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. Methods: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. Main body: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. Conclusion: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics
Repeated nicotine exposure modulates prodynorphin and pronociceptin levels in the reward pathway
No full textBackground Nicotine dependence is maintained by neurobiological adaptations in the dopaminergic brain reward pathway with the contribution of opioidergic circuits. This study assessed the role of opioid peptides and receptors on the molecular changes associated with nicotine dependence. To this aim we analysed nicotine effects on opioid gene and receptor expression in the reward pathway in a nicotine sensitization model. Methods Sprague-Dawley rats received nicotine administrations for five days and locomotor activity assessment showed the development of sensitization. The mRNA expression of prodynorphin (pdyn), pronociceptin (pnoc) and the respective receptors was measured by quantitative PCR in the ventral midbrain (VM), the nucleus accumbens (NAc), the caudate-putamen (CPu), the pre-frontal cortex (PFCx), and the hippocampus. Results A significant positive effect of sensitization on pdyn mRNA levels was detected in the CPu. This effect was supported by a significant and selective correlation between the two parameters in this region. Moreover, chronic but not acute nicotine treatment significantly decreased pdyn mRNA levels in the NAc and increased expression in the PFCx. Pnoc mRNA was significantly increased in the VM and the PFCx after sub-chronic administration of nicotine, whereas no alterations were observed after acute treatment. No treatment associated changes were detected in κ-opioid receptor or nociceptin receptor mRNAs. Conclusions This experiment revealed an effect of nicotine administration that was distinguishable from the effect of nicotine sensitization. While several pnoc and pdyn changes were associated to nicotine administration, the only significant effect of sensitization was a significant increase in pdyn in the CPu
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