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. 

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

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

New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation

DMSO is one of the most common solvents used experimentally to dissolve hydrophobic substances for in vivo and in vitro purposes. A wide range of pharmacological effects exerted by DMSO has been documented in both animal and human experimental models. However, only a few and sometimes contrasting data about the effects of DMSO in animal models of nociception and inflammation are presently available. In this study, we evaluated the effects induced by DMSO and a DMSO-containing saline on thermal and chemical nociception, inflammation and locomotor activity in CD1 mice. We demonstrated that centrally or orally administered DMSO displayed anti-nociceptive effects to thermal (hot plate and tail-flick test) and chemical (formalin test) stimuli. Conversely, DMSO was able to increase both nociceptive phases in the formalin test when applied subcutaneously in the dorsal surface of the mouse hind paws 10 min before formalin administration. Oral administration of DMSO produced anti-inflammatory effects on zymosan-induced edema in the mouse paw, whereas local administration potentiated the inflammatory action exerted by zymosan. Oral and central, but not local, administration of DMSO improved the mouse locomotor activity. These results suggest that DMSO displayed opposite effects on nociception and inflammation, depending on the route of administration. New and helpful evidence about DMSO laboratory applications need to be considered in the in vivo studies to assess correctly the pharmacological properties of investigated drugs

“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

Effect of PDGF, IGF-1 and PRP on the implant osseointegration. An histological and immunohistochemical study in rabbits

The ability of platelet-derived growth factor(PDGF), insulin-like growth factor-1 (IGF-1) and platelet-rich plasma (PRP) to increase the rate of osseointegration of endosseous implants and to improve the quality of bone remodeling on the surface of titanium, has been investigated in an experimental intraosseous defect model by an histological and immunohistochemical evaluation. The results from this study demonstrate that rabbits treated with the combination PDGF/IGF-1 showed a higher positive effect on bone regeneration than PRP-treated or controls

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

Enhanced antinociceptive and anti-inflammatory effects of ibuprofen encapsulated in niosomal vesicles

The non-steroidal anti-inflammatory (NSAID) drug Ibuprofen (α-methyl-4-(2-methylpropyl)-benzeneacetic acid), is widely used in the treatment of pain, fever and inflammatory diseases. As far as its analgesic actions, ibuprofen inhibits the production of prostanoids, which mediate peripheral and central pain sensation, reducing the threshold to stimulation of nociceptors and increasing their terminal membrane excitability [1]. Niosomes, are unilamellar or multilamellar non-ionic surfactant vesicles. The main characteristic of these vesicles is their capability of encapsulating both lipophilic and hydrophilic drugs; hydrophilic drugs are encapsulated in the core of vesicles, while lipophilic drugs can be encapsulated into the lipophilic domain of the lipid bilayer [2]. In this work, we evaluated the analgesic activity of subcutaneous injection (s.c) of ibuprofen loaded TW20Gly niosomes (N-IBU), in comparison with free ibuprofen (IBU) in acute and chronic pain animal models. In vivo anti nociceptive activities of Ibuprofen-loaded vesicles were preliminarily tested by performing the writing and capsaicin screening assays. In writhing test, acetic acid as peripheral pain inducer was utilized. Analgesic activity was determined by entering the reduction of the number of writhes after acetic acid injection. In the early tested mice, a statistically significant reduction of writhes was observed only in IBU branch, whereas in the late tested mice the strongest reduction was observed in N[IBU] treated mice. In capsaicin experiments, in which mice were injected under the hind paw with capsacin, nociceptive activity was evaluated by measuring the time spent by mice in licking the injected paw. N-IBU significantly decreased capsaicin-induced paw licking, while IBU was ineffective. N-IBU also induced the strongest antinociceptive effects in Zymosan-induced hyperalgesia test. N-IBU increased pain threshold also in a model of neuropathic pain i.e. chronic sciatic nerve ligation, reducing hypealgesia and allodyia 2h after the treatment up to 4h. In the same conditions IBU did not gave any significant effect. We can conclude that the encapsulation of the drug into the niosomes significantly increases IBU analgesic activity, promoting a long lasting action of this drug. Thus, we propose TW20Gly niosomes as a new and more effective strategy to vehicle IBU to treat acute and chronic pain conditions. _____________________________________ 1. Brunton LL, Chabner BA, Knollman BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw- Hill Medical; 2011. 2. Di Marzio L, Marianecci C, Petrone M, Rinaldi F, Carafa M., Colloids Surf B Biointerfaces 2011, 82(1), 18

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

Guinea pig ileum motility stimulation elicited by N-formyl-Met-Leu-Phe (fMLF) involves neurotransmitters and prostanoids

In guinea-pig ileum (GPI), the chemotactic peptide N-formyl-Met-Leu-Phe-OH (fMLF) possesses spasmogenic properties through the activation of formyl peptide receptors (FPRs). Despite this, the mediators involved remain to be elucidated. fMLF (1 nM-1 mu M) induced a dose-dependent contraction of GPI (EC(50) = 24 nM), that is blocked by pre-treatment with the FPRs antagonist Boc(2). The pre-treatment with tetrodotoxin (TTX) atropine or with SR140333 reduced the fMLF-induced contraction, whereas with hexamethonium, MEN10627, SB222200, mepyramine, cimetidine, thioperamide or methysergide did not produce any effect. With DuP697 pre-treatment, but not with piroxicam, reduced the fMLF-induced contraction. After stimulation with 24 nM fMLF, a strong increase in the PGE(2) levels was observed. Finally, the concomitant blocking of the NK(1) receptor, the muscarinic receptors and COX-2 abolished the GPI contractions induced by fMLF. fMLF induced a concentration-dependent contraction of guinea-pig jejunum (EC(50) = 11 nM), proximal colon (EC(50) = 3.5 nM) and distal colon (EC(50) = 2.2 nM), with a time-course similar to that observed in GPI. In these preparations as well, the co-administration of atropine, SR140333 and DuP697 abolished the contractions induced by fMLF. Intraperitoneal injection of fMLF (0.1 or 1 mu mol/kg) enhanced the gastrointestinal motility in mice, abolished by the co-administration of atropine, SR140333 and DuP697. In conclusion, we showed that fMLF exerts spasmogenic actions on guinea-pig intestine both in vitro and in vivo through the release of acetylcholine and substance P from myenteric motorneurons and through prostanoids, probably from the inflammatory cells of the enteric immune system. (C) 2010 Elsevier Inc. All rights reserved