Gender differences in pain and its relief

There is much evidence to suggest that gender is an important factor in the modulation of pain. Literature data strongly suggest that men and women differ in their responses to pain: they are more variable in women than men, with increased pain sensitivity and many more painful diseases commonly reported among women. Gender differences in pharmacological therapy and non-pharmacological pain interventions have also been reported, but these effects appear to depend on the treatment type and characteristics. It is becoming very evident that gender differences in pain and its relief arise from an interaction of genetic, anatomical, physiological, neuronal, hormonal, psychological and social factors which modulate pain differently in the sexes. Experimental data indicate that both a different modulation of the endogenous opioid system and sex hormones are factors influencing pain sensitivity in males and females. This brief review will examine the literature on sex differences in experimental and clinical pain, focusing on several biological mechanisms implicated in the observed gender-related differences. 

On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity

Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.University of ArizonaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation. © 2016 Informa UK Limited, trading as Taylor & Francis Group

La collaborazione tra istituzioni scolastiche e territorio \u200bper la promozione dell\u2019impegno civico e sociale

L\u2019articolo presenta e discute come le istituzioni scolastiche, in collaborazione con il territorio, sostengono lo sviluppo di impegno civico e sociale negli studenti e nelle studentesse di scuola primaria, secondaria e di istruzione di base per adulti. A partire dall\u2019analisi di 21 articoli individuati attraverso una revisione sistematica della letteratura internazionale sono state identificate induttivamente le tipologie di pratiche educative prevalenti. I risultati mostrano come tali pratiche si rivolgano primariamente a studenti e studentesse in et\ue0 scolare, e solo limitatamente agli utenti del sistema di istruzione di base per adulti, e che coinvolgono per lo pi\uf9 la \u2018comunit\ue0 locale\u2019, anzich\ue9 la \u2018comunit\ue0 allargata\u2019. Inoltre, anche se derivati da studi condotti con metodi e scopi differenti, i risultati permettono alcune considerazioni generali su: la declinazione dell\u2019impegno civico e sociale; gli effetti delle pratiche educative sull\u2019impegno civico e sociale di quanti in esse coinvolti; e gli elementi che possono supportarne la riuscita.This article presents and discusses the results of a systematic review on the role of schools (from primary to adult education) in enhancing students\u2019 civic engagement through collaboration with community. Based on the analysis of 21 selected studies, the authors inductively identified the main educational practices aimed at improving civic engagement. The results show that these practices are aimed primarily at school-age students, and only to a limited extent to adult students, as well as that they mostly involve the \u2018local\u2019 more than the \u2018global\u2019 community. Albeit derived from studies conducted with different methods and purposes, the results also allow some general considerations on the definition of civic engagament, the effects of educational practices on students\u2019 civic engagement and the factors that facilitate the effectiveness of such practices

Gender differences in pain and its relief

There is much evidence to suggest that gender is an important lactor in the modulation of pain. Literature data strongly suggest that men and women differ in their responses to pain: They are more variable in women than men, with increased pain sensitivity and many more painful diseases commonly reported among women. Gender differences in pharmacological therapy and non-pharmacological pain interventions have also been reported, but these cffccts appear to depend on the treatment type and characteristics. It is becoming very evident that gender differences in pain and its relief arise from an interaction of genetic, anatomical, physiological, neuronal, hormonal, psychological and social factors which modulate pain differently in the sexes. Experimental data indicate that both a different modulation of the endogenous opioid system and sex hormones are factors influencing pain sensitivity in males and females. This brief review will examine the literature on sex differences in experimental and clinical pain, focusing on several biological mechanisms implicated in the observed gender-related differences

Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice

Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes mellitus, leading to painful condition as neuropathic pain. The pathogenetic mechanism of diabetic peripheral neuropathy is very complex, and its understanding could lead to a more suitable therapeutic strategy. In this work, we analyzed the effects of ammonium glycyrrhizinate, a derivate salt of glycyrrhizic acid, on an in vitro system, neuroblastoma cells line SH-SY5Y, and we observed that ammonium glycyrrhizinate was able to prevent cytotoxic effect and mitochondrial fragmentation after high-glucose administration. In an in vivo experiment, we found that a short-repeated treatment with ammonium glycyrrhizinate was able to attenuate neuropathic hyperalgesia in streptozotocin-induced diabetic mice. In conclusion, our results showed that ammonium glycyrrhizinate could ameliorate diabetic peripheral neuropathy, counteracting both in vitro and in vivo effects induced by high glucose, and might represent a complementary medicine for the clinical management of diabetic peripheral neuropathy

Curcumin-loaded Poly (d,l-lactide-co-glycolide) nanovesicles induce antinociceptive effects after local administration in mice

Both acute and chronic pain are the most widespread medical issue strongly affecting people in terms of health and quality of life. Unlike acute pain, chronic pain is a pathophysiological state arising from the alteration of the peripheral and/or central nervous systems. It is frequently accompanied by the onset of hyperalgesia (increased sensitivity to pain) and allodynia (painful sensation in response to usually innocuous stimuli). Pain is currently treated with two major groups of analgesic drugs, namely non-steroidal anti-inflammatory drugs (NSAIDs) and opioids; their use is associated with important side effects, which include gastrointestinal lesions [1] and nephrotoxicity [2]; in the case of NSAIDs, respiratory depression, tolerance and physical dependence for opioids [3]. For this reason, there is growing interest for the identification of alternative therapeutic strategies. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a yellow polyphenol, diferuloylmethane, extracted from the rhizomes of turmeric (Curcuma longa)[4]. The therapeutic properties of curcumin are well known indeed possesses low intrinsic toxicity along with a wide range of pharmacological activities that include antitumor, anti-amyloid, antioxidant and anti-inflammatory capacities [5]. Antinociceptive properties of curcumin have also been reported in preclinical studies [6], but its poor bioavaibility limits clinical use as analgesic. Polymeric nanoparticle-based drug delivery is being increasingly investigated as a delivery route able to overcome many obstacles associated with the delivery of free drugs. Recently, we investigated the effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes in several experimental models of pain [7]. We found that i.v. or i.t. routes of administration of PLGA-CUR nanoformulations were effective in reducing the nociception induced by chemical stimuli or after the ligation of the sciatic nerve in mice [7]. In the present study, putative antinociceptive effects induced by CUR and PLGA-CUR after local subcutaneous administration was investigated in two animal models of pain i.e. the formalin test and the hyperalgesia induced by zymosan. We found PLGA-CUR vesicles able to reduce nociception induced by chemical stimuli, whereas CUR alone induced only a transient but not significant antinociceptive effects. These results obtained after acute subcutaneous local PLGA-CUR vesicles administration, further suggest that PLGA-CUR formulation should be developed as a new potential drug in the treatment of pain in humans. _____________________________________ 1. M. Sinha, L. Gautam, P.K. Shukla et al., Mediators Inflamm., 2013, 258209. 2. M. Musu, G. Finco, R. Antonucci et al., Eur. Rev. Med. Pharmacol. Sci, 2011, 15, 1461. 3. R. Benyamin, A.M. Trescot, S. Datta et al., Pain Physician, 2018, S105. 4. S.C. Gupta, G. Kismali, B.B. Aggarwal, Biofactors, 2013, 39, 2. 5. S. Sharma, S.K. Kulkarni, J.N. Agrewala et al., Eur. J. Pharmacol., 2006, 536, 256. 6. L. Allegri, F. Rosignolo,C. Mio et al., J. Cancer Res. Clin. Oncol. 2018, 144, 285. 7. S. Pieretti, A.P. Ranjan, A. Di Giannuario et al., Colloids Surf B Biointerfaces, 2017, 158, 379

Antinociceptive effects of Curcumin-loaded PLGA vesicles

Curcumin is yellow polyphenol, extracted from the rhizomes of turmeric (Curcuma longa) and used in traditional medicine for many centuries in countries such as India and China (1). Curcumin demonstrated a wide range of pharmacological activities that include antitumor, anti-amyloid, antioxidant, anti-inflammatory properties and analgesia. At present, no data are reported in the literature on the antinociceptive effects induced by curcumin loaded in PLGA vesicles (PLGA-CURC) and we investigated first the effects of PLGA-CURC in acute models of pain after systemic and central administration. Male CD-1 mice (Harlan, Italy) weighing 25-30 g were used for all experiments. The research protocol was authorized by the Italian Ministry of Health, according to Legislative Decree 26/14. Subcutaneous injection of a dilute solution of formalin (1%, 20 μl/paw) into the mice hind paw evokes nociceptive behavioral responses, such as licking, biting the injected paw or both, which are considered indices of nociception (2). The nociceptive response shows a biphasic trend, consisting of an early phase occurring from 0 to 10 min after the formalin injection, due to the direct stimulation of peripheral nociceptors, followed by a late prolonged phase occurring from 15 to 40 min, that reflects the response to inflammatory pain. The total time (s) that the animal spent licking or biting its paw during the formalin-induced early and late phase of nociception was recorded. In the first series of experiments curcumin-vehicle, curcumin, blank-PLGA and curcumin-PLGA (0.045 mg curcumin/mg of nanoparticles, a generous gift of dr. A. Ranjan, University of North Texas Health Science Center, Fort Worth, TX, USA) were administered i.v. at the dose of 20 mg/kg, in curcumin. In the second series of experiments curcumin-vehicle, curcumin, blank-PLGA and curcumin-PLGA were administered i.t. at doses of 5 and 25 g/mouse, in curcumin. The significance among the groups (P<0.05) was evaluated with ANOVA followed by Tukey’s post-hoc comparisons using GraphPad Prism 6.03 software. After i.v. treatment, ANOVA revealed no difference between groups in the early phase of the formalin test. On the contrary, in the late phase of the test i.v. curcumin-PLGA was able to strongly reduced the nociceptive behavior induced by formalin. After i.t. administration at the dose of 5 g/mouse, treatments did not change licking behavior induced by formalin neither in the early nor in the late phase of the test. After i.t. administration at the dose of 25 g/mouse, curcumin-PLGA was able to reduce licking activity - in confront to curcumin-vehicle and blank-PLGA treated animals - both in the early and in the late phase of the test. These data suggest that curcumin-PLGA may be developed as a medicine to treat pain, by warranting further rigorously conducted studies to define the long-term efficacy and safety. 1. P. Anand, S.G. Thomas, A.B. Kunnumakkara, C. Sundaram, K.B. Harikumar, B.Sung, S.T.Tharakan, K. Misra, I.K. Priyadarsini, K.N. Rajasekharan, B.B. Aggarwal, Biochem. Pharmacol. 2008, 76, 1590. 2. M. Colucci, F. Maione, M.C. Bonito, A. Piscopo, A. Di Giannuario, S. Pieretti, Pharmacol Res., 2008, 57, 419

“Glycyrrhizic Acid attenuates the cytotoxicity induced by high glucose in neuroblastoma cell line”

Glycyrrhizic Acid attenuates the cytotoxicity induced by high glucose in neuroblastoma cell lin

Prolongation of local pain insensitivity by anesthetic lidocaine loaded pH-TW20 Gly niosomes: effects on nociception in murine models of pain

Current drugs treating neuropathic pain fail in up to 40-50% of the patients, because they have limited efficacy and are associated with dose related unwanted adverse effects [1]. One of the most extensively studied agents for neuropathic pain in animals and humans is lidocaine, a local anesthetic with a short duration of action [2]. The great interest in lidocaine delivery systems is increased in the last years. The final purpose is to prolong the effective time of lidocaine and to reduce the frequency of administration. Particularly, pH-sensitive molecules to niosome formulation represents an effective and promising delivery strategy [3]. pH-sensitive nonionic surfactant vesicles (niosomes) by polysorbate-20 derivatized by glycine (added as pH sensitive agent), were developed to deliver Lidocaine (LID). Lidocaine (5%) were chosen into niosome (N[LID]) (TW20-GLY LIDO 5%) [3]. Experiments to assess the in vivo efficacy of lidocaine loaded pH-TW20 GLY niosomes were carried out in murine models to evaluate the potential advantages of stimuli responsive nanocarriers, loaded with lidocaine in pain treatments. The data related to these tests and obtained from lidocaine loaded pH-TW20 Gly niosomes were compared with those obtained from free lidocaine, in order to highlight the overlap with the data. The following models of pain were used: formalin test, zymosan-induced hyperalgesia, Tail flick test and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. The subcutaneous administration of N[LID] in the dorsal surface of mice paw 10 min or 180 min before formalin in a volume of 40 μL/paw and 1h after zymosan A in a same volume was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. The already high effects of free lidocaine were improved in terms of higher duration of its action over time. The results obtained by Tail flick test confirmed that N[LID] has a longer analgesic effect than free lidocaine, especially in terms of longer duration of action. Experience to date suggests that 40 μL/paw s.c. administration of N[LID] significantly reduced allodynia and hyperalgesia produced by sciatic nerve ligation. Niosome represents an effective and promising delivery strategy, which may greatly increase the utility of niosomes as a targeted delivery vehicle, which is degraded only in the target area, where the drug will be released and accumulated. In our opinion, N[LID] should be developed as a new potential drug in the treatment of pain in humans. _____________________________________ 1. Y.B. Martin, G. Herradón, L. Ezquerra, Curr Pharm Des., 2011, 17, 434. 2. C.P.N. Watson, Progress in Pain Research and Management, 2001, 21, 215. 3. F. Rinaldi, E. Del Favero, V. Rondelli, S. Pieretti, A. Bogni, J. Ponti, F. Rossi, L. Di Marzio, D. Paolino, J Enzyme Inhib Med Chem., 2017, 32, 538