Electroacupuncture attenuates nociceptive behaviors in a mouse model of cancer pain.

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.

A novel microglia-targeting strategy based on nanoparticle-mediated delivery of miR-26a-5p for long-lasting analgesia in chronic pain.

Accumulating evidence supports the notion that microglia play versatile roles in different chronic pain conditions. However, therapeutic strategies of chronic pain by targeting microglia remain largely overlooked. This study seeks to develop a miRNA-loaded nano-delivery system by targeting microglia, which could provide a decent and long-lasting analgesia for chronic pain. Surface aminated mesoporous silica nanoparticles were adopted to load miR-26a-5p, a potent analgesic miRNA, by electrostatic adsorption, which can avoid miR-26a-5p is rapidly released and degraded. Then, targeting peptide MG1 was modified on the surface of aminated mesoporous silica particles for microglia targeting. In peripheral nerve injury induced neuropathic pain model, a satisfactory anti-allodynia effect with about 6 weeks pain-relief duration were achieved through targeting microglia strategy, which decreased microglia activation and inflammation by Wnt5a, a non-canonical Wnt pathway. In inflammatory pain and chemotherapy induced peripheral neuropathic pain, microglia targeting strategy also exhibited more efficient analgesia and longer pain-relief duration than others. Overall, we developed a microglia-targeting nano-delivery system, which facilitates precisely miR-26a-5p delivery to enhance analgesic effect and duration for several chronic pain conditions.

Benzydamine plays a role in limiting inflammatory pain induced by neuronal sensitization.

Benzydamine is an active pharmaceutical compound used in the oral care pharmaceutical preparation as NSAID. Beside from its anti-inflammatory action, benzydamine local application effectively reliefs pain showing analgesic and anaesthetic properties. Benzydamine mechanism of action has been characterized on inflammatory cell types and mediators highlighting its capacity to inhibit pro-inflammatory mediators' synthesis and release. On the other hand, the role of benzydamine as neuronal excitability modulator has not yet fully explored. Thus, we studied benzydamine's effect over primary cultured DRG nociceptors excitability and after acute and chronic inflammatory sensitization, as a model to evaluate relative nociceptive response. Benzydamine demonstrated to effectively inhibit neuronal basal excitability reducing its firing frequency and increasing rheobase and afterhyperpolarization amplitude. Its effect was time and dose-dependent. At higher doses, benzydamine induced changes in action potential wavelength, decreasing its height and slightly increasing its duration. Moreover, the compound reduced neuronal acute and chronic inflammatory sensitization. It inhibited neuronal excitability mediated either by an inflammatory cocktail, acidic pH or high external KCl. Notably, higher potency was evidenced under inflammatory sensitized conditions. This effect could be explained either by modulation of inflammatory and/or neuronal sensitizing signalling cascades or by direct modulation of proalgesic and action potential firing initiating ion channels. Apparently, the compound inhibited Nav1.8 channel but had no effect over Kv7.2, Kv7.3, TRPV1 and TRPA1. In conclusion, the obtained results strengthen the analgesic and anti-inflammatory effect of benzydamine, highlighting its mode of action on local pain and inflammatory signalling.

Intrathecal Injection of Botulinum Toxin Type A has an Analgesic Effect in Male Rats CCI Model by Inhibiting the Activation of Spinal P2X4R.

Purinergic receptor P2X4 (P2X4R) plays an essential role in neuropathic pain. However, the specific mechanism needs to be clarified. Botulinum toxin type A is a neurotoxin produced by Clostridium botulinum type A. This study found that intrathecal injection of botulinum toxin type A produced an excellent analgesic effect in a rat model of chronic constriction sciatic nerve injury and inhibited the activation of P2X4R, microglia, and astrocytes. The administration of a P2X4R activator can up-regulate the expression of P2X4R and eliminate the analgesic effect of intrathecal injection of botulinum toxin type A. In addition, we found that microglia and astrocytes in the spinal cord of rats injected with botulinum toxin type A were reactivated after administration of the P2X4R activator. Our results suggest that intrathecal injection of botulinum toxin type A has an analgesic effect in a rat model of chronic constriction sciatic nerve injury by inhibiting the activation of P2X4R in the spinal cord.

Analgesic effect of gastrin-releasing peptide in the dorsal horn.

Itch and pain are both unpleasant, but they are discrete sensations. Both of these sensations are transmitted by C-fibers and processed in laminae I-II of the dorsal horn. To examine whether pruriception modulates pain, we first confirmed the activation of cells in the itch-related circuits that were positive for gastrin-releasing peptide (GRP) and GRP receptor (GRPR) using a paw formalin injection model. This pain model with typical biphasic pain behavior increased c-Fos but did not affect the expressions of GRP and GRPR mRNAs in the dorsal horn. Using c-Fos expression as a marker for activated cells, we confirmed that formalin injection increased the number of cells double-labeled for c-Fos and GRP or GRPR in the dorsal horn. The emergence of these neurons indicates the activation of itch-related circuits by acute pain signals. The effect of an antagonist for a GRPR was examined in the paw formalin injection model. Intrathecal chronic antagonization of spinal GRPR enhanced the onset of phase II of paw formalin injection-induced pain behavior. Exogenous intrathecal GRP infusion to the paw-formalin injection model not only showed significant reduction of pain behavior but also increased c-Fos in the inhibitory neurons in the dorsal horn. The anti-nociceptive effect of spinal GRP infusion was observed in the peripheral inflammation model (complete Freund's adjuvant injection model). In this study we suggest that painful stimuli activated itch-related neuronal circuits and uncovered the spinal activation of the itch-induced analgesic effect on acute and established inflammatory pain.

The analgesic effects of ß-elemene in rats with neuropathic pain by inhibition of spinal astrocytic ERK activation.

Neuropathic pain takes a heavy toll on individual well-being, while current therapy is far from desirable. Herein, we assessed the analgesic effect of ß-elemene, a chief component in the traditional Chinese medicine Curcuma wenyujin, and explored the underlying mechanisms at the level of spinal dorsal horn (SDH) under neuropathic pain. A spared nerve injury (SNI)-induced neuropathic pain model was established in rats. Intraperitoneal injection (i.p.) of ß-elemene was administered for 21 consecutive days. Mechanical allodynia was explored by von Frey filaments. The activation of the mitogen-activated protein kinase (MAPK) family (including ERK, p38, and JNK) in spinal neurons, astrocytes, and microglia was evaluated using immunostaining 29 days after SNI surgery. The expression of GFAP, Iba-1, p-ERK, p-JNK, and p-p38 within the SDH was measured using immunoblotting. The levels of proinflammatory cytokines (including TNF-α, IL-1ß, and IL-6) were measured with ELISA. The levels of oxidative stress indicators (including MDA, SOD, and GSH-PX) were detected using biochemical tests. Consecutive i.p. administration of ß-elemene relieved SNI-induced mechanical allodynia (with an EC50 of 16.40 mg/kg). SNI significantly increased the expression of p-ERK in spinal astrocytes but not microglia on day 29. ß-elemene reversed spinal astrocytic ERK activation and subsequent upregulation of proinflammatory cytokines in SNI rats, with no effect on the expression of p38 and JNK in spinal glia. ß-elemene also exerted antioxidative effects by increasing the levels of SOD and GSH-PX and decreasing the level of MDA. Our results suggest that SNI induces robust astrocytic ERK activation within the SDH in the late phase of neuropathic pain. ß-elemene exerts remarkable analgesic effects on neuropathic pain, possibly by inhibiting spinal astrocytic ERK activation and subsequent neuroinflammatory processes. Our findings suggest that ß-elemene might be a promising analgesic for the treatment of chronic pain.

Analgesic effects of Terminalia chebula extract are mediated by the suppression of the protein expression of nerve growth factor and nuclear factor-κB in the brain and oxidative markers following neuropathic pain in rats.

BACKGROUND: Due to the complications related to the use of the current pharmacological approach for the alleviation of neuropathic pain, searching for effective compound with fewer complications is a requirement of the present era. It is well known that the pathophysiological mechanism of neuropathic pain is related to excessive inflammation in the nervous system. Hence, the present study focuses on whether the potential analgesic effects of Terminalia chebula (TC) extract are mediated by the changes in the protein expression of nerve growth factor (NGF) and nuclear factor-kappa B (NF-κB) in the brain in a rat model of sciatic nerve chronic constriction injury (CCI). METHOD AND RESULTS: Neuropathic pain was induced by the left sciatic nerve CCI. Male Wistar rats were assigned to three groups: sham, CCI, and CCI + TC (40 mg/kg). Animals received either normal saline (1 mL) or the aqueous-alcoholic extract of TC (40 mg/kg) for 30 days via gavage needles once a day. Cold allodynia and anxiety-like behaviors were examined one day before CCI surgery (day - 1), as well as days 2, 7, 14, and 30 following CCI. We also assessed the effects of the TC extract oxidative stress markers on day 30 following CCI. Moreover, a western blot analysis was performed on day 30 following CCI to evaluate the effects of the TC extract on the protein expression of NGF and NF-κB in the brain. Oral gavage of the TC extract significantly decreased cold allodynia on days 2 and 14 following CCI. Additionally, the CCI model of chronic pain significantly increased the protein expression of NGF and NF-κB in the brain on day 30 following CCI. Furthermore, the TC extract significantly decreased the protein expression of NGF and NF-κB in the brain. The TC extract also significantly increased the brain glutathione (GSH) content and decreased the malondialdehyde (MDA) content. CONCLUSION: It is suggested that the analgesic effects of the TC extract are mediated by the suppression of brain NGF, NF-κB, and by its antioxidant activity in the brain following neuropathic pain in rats.

Metabolites of Cannabis Induce Cardiac Toxicity and Morphological Alterations in Cardiac Myocytes.

Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250-100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel.

Neuropathic pain is a refractory chronic disease affecting millions of people worldwide. Given that present painkillers have poor efficacy or severe side effects, developing novel analgesics is badly needed. The multiplex structure of active ingredients isolated from natural products provides a new source for phytochemical compound synthesis. Here, we identified a natural product, Narirutin, a flavonoid compound isolated from the Citrus unshiu, showing antinociceptive effects in rodent models of neuropathic pain. Using calcium imaging, whole-cell electrophysiology, western blotting, and immunofluorescence, we uncovered a molecular target for Narirutin's antinociceptive actions. We found that Narirutin (i) inhibits Veratridine-triggered nociceptor activities in L4-L6 rat dorsal root ganglion (DRG) neurons, (ii) blocks voltage-gated sodium (NaV) channels subtype 1.7 in both small-diameter DRG nociceptive neurons and human embryonic kidney (HEK) 293 cell line, (iii) does not affect tetrodotoxin-resistant (TTX-R) NaV channels, and (iv) blunts the upregulation of Nav1.7 in calcitonin gene-related peptide (CGRP)-labeled DRG sensory neurons after spared nerve injury (SNI) surgery. Identifying Nav1.7 as a molecular target of Narirutin may further clarify the analgesic mechanism of natural flavonoid compounds and provide an optimal idea to produce novel selective and efficient analgesic drugs.

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems.

Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for ß-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.

Pharmacology and Mechanism of Action of HSK16149, a Selective Ligand of α2δ Subunit of Voltage-Gated Calcium Channel with Analgesic Activity in Animal Models of Chronic Pain.

Chronic pain is a public health problem because current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited because of its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) α 2 δ subunit. HSK16149 inhibited [3H]gabapentin binding to the α 2 δ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg, and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 hours postadministration at 30 mg/kg, whereas the efficacy of pregabalin lasted only for 12 hours at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, whereas in the Rotarod test, the MEDs of HSK16149 and pregabalin were 100 and 30 mg/kg, respectively. These findings indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC α 2 δ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. SIGNIFICANCE STATEMENT: As a novel potent ligand of voltage-gated calcium channel α 2 δ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.

Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects.

BACKGROUND: The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine. METHODS: Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis. RESULTS: After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations-time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers. CONCLUSIONS: Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion.

Butyl methyl imidazolium silica sulfate (BMIm)SS: A novel hybrid nano-catalyst for highly efficient synthesis of new 1,2-diol monoesters of ibuprofen as the novel prodrugs of ibuprofen having potent analgesic property.

The fabrication, characterization of butyl methyl imidazolium silica sulfate [BMIm]SS as a novel nano hybrid catalyst and its application in synthesis of new ibuprofen (IBP) 1,2-diol mono esters were described. [BMIm]SS catalyzed the reaction of IBP with epoxides to afford the new IBP 1,2-diol mono esters in good to excellent yields. The products were tested in vivo for the analgesic properties on female mice using formalin test. The test results revealed that most compounds, in particular compounds 1h, 1k and 1o displayed potent analgesic activity compare to IBP as a reference drug. No mortality was observed due to the toxicity of the synthesized compounds. The docking analysis was conducted that confirmed the strong binding affinity of active compounds to active site of murine cyclooxygenase-2 (COX-2) enzyme compare to IBP. The in silico pharmacokinetic profile, drug likeness and toxicity predictions were carried out for all compounds which determined that 1h can be suggested as an appropriate future drug candidate.

Biphalin-A Potent Opioid Agonist-As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Atractylodin Produces Antinociceptive Effect through a Long-Lasting TRPA1 Channel Activation.

Atractylodin (ATR) is a bioactive component found in dried rhizomes of Atractylodes lancea (AL) De Candolle. Although AL has accumulated empirical evidence for the treatment of pain, the molecular mechanism underlying the anti-pain effect of ATR remains unclear. In this study, we found that ATR increases transient receptor potential ankyrin-1 (TRPA1) single-channel activity in hTRPA1 expressing HEK293 cells. A bath application of ATR produced a long-lasting calcium response, and the response was completely diminished in the dorsal root ganglion neurons of TRPA1 knockout mice. Intraplantar injection of ATR evoked moderate and prolonged nociceptive behavior compared to the injection of allyl isothiocyanate (AITC). Systemic application of ATR inhibited AITC-induced nociceptive responses in a dose-dependent manner. Co-application of ATR and QX-314 increased the noxious heat threshold compared with AITC in vivo. Collectively, we concluded that ATR is a unique agonist of TRPA1 channels, which produces long-lasting channel activation. Our results indicated ATR-mediated anti-nociceptive effect through the desensitization of TRPA1-expressing nociceptors.

Chemical Profiles and Pharmacological Properties with in Silico Studies on Elatostema papillosum Wedd.

The current study attempted, for the first time, to qualitatively and quantitatively determine the phytochemical components of Elatostema papillosum methanol extract and their biological activities. The present study represents an effort to correlate our previously reported biological activities with a computational study, including molecular docking, and ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analyses, to identify the phytochemicals that are potentially responsible for the antioxidant, antidepressant, anxiolytic, analgesic, and anti-inflammatory activities of this plant. In the gas chromatography-mass spectroscopy analysis, a total of 24 compounds were identified, seven of which were documented as being bioactive based on their binding affinities. These seven were subjected to molecular docking studies that were correlated with the pharmacological outcomes. Additionally, the ADME/T properties of these compounds were evaluated to determine their drug-like properties and toxicity levels. The seven selected, isolated compounds displayed favorable binding affinities to potassium channels, human serotonin receptor, cyclooxygenase-1 (COX-1), COX-2, nuclear factor (NF)-κB, and human peroxiredoxin 5 receptor proteins. Phytol acetate, and terpene compounds identified in E. papillosum displayed strong predictive binding affinities towards the human serotonin receptor. Furthermore, 3-trifluoroacetoxypentadecane showed a significant binding affinity for the KcsA potassium channel. Eicosanal showed the highest predicted binding affinity towards the human peroxiredoxin 5 receptor. All of these findings support the observed in vivo antidepressant and anxiolytic effects and the in vitro antioxidant effects observed for this extract. The identified compounds from E. papillosum showed the lowest binding affinities towards COX-1, COX-2, and NF-κB receptors, which indicated the inconsequential impacts of this extract against the activities of these three proteins. Overall, E. papillosum appears to be bioactive and could represent a potential source for the development of alternative medicines; however, further analytical experiments remain necessary.

Continuous infusion of substance P inhibits acute, but not subacute, inflammatory pain induced by complete Freund's adjuvant.

Previous studies have reported that continuous infusion with substance P (SP) into rat dorsal striatum ameliorated both mechanical allodynia in both formalin-evoked transient inflammatory pain and neuropathic pain models. However, a role of striatal SP in persistent inflammatory pain has not been demonstrated. The current study examined the effect of continuous infusion of SP into the rat dorsal striatum by reverse microdialysis on persistent inflammatory pain induced by complete Freund's adjuvant (CFA). Intraplantar injection of CFA evoked both mechanical allodynia and paw edema 3 and 7 days post-injection. The continuous infusion of SP ameliorated the CFA-evoked mechanical allodynia, but not paw edema, 3 days after the CFA injection. This antinociceptive effect of SP was partially inhibited by co-infusion with the neurokinin-1 (NK1) receptor antagonist CP96345. Conversely, at 7 days both CFA-evoked mechanical allodynia and paw edema were not affected by SP treatment. To clarify why the effect of SP treatment on CFA-induced pain changed, we evaluated NK1 receptor protein levels at both time points. The NK1 receptor protein level was decreased at 7, but not 3, days post CFA injection. These data suggest that persistent inflammatory pain can downregulate the striatal NK1 receptor. The current study demonstrates that striatal SP-NK1 receptor pathway can exert antinociceptive effect only on the third days of inflammatory pain phase defined as an acute but not the 7 days defined as a subacute.

Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis.

Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months-15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92-1.09) and in CSF (range 0.64-1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64-1.66, range AUCo/AUCp CSF: 1.43-1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS.

Peripherally acting opioid analgesics and peripherally-induced analgesia.

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.

Screening of chalcone analogs with anti-depressant, anti-inflammatory, analgesic, and COX-2-inhibiting effects.

A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a-2x) was synthesized and investigated for anti-depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experiments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In particular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-2 inhibitory effects (IC50 values from 0.21 to 0.29 µmol/L) similar to celecoxib (IC50: 0.19 µmol/L) in vitro. A molecular docking study of compound 2k also was conducted.