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Francisco Pellicer,1 Juan M Ortega-Legaspi,2 Rodrigo Martín,3 Sergio Solís-Nájera,4 Lucía Magis-Weinberg,5 Martha León-Olea,6 Ariel Graff-Guerrero,7,8 Camilo de la Fuente-Sandoval,9 Alfredo O Rodriguez3 1Laboratorio de Neurofisiología Integrativa, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 2Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 3Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana Iztapalapa, CDMX, México; 4Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, México; 5Department of Psychology, University of Washington Guthrie Hall (GTH), Seattle, WA, USA; 6Departamento de Neuromorfología Funcional, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 7Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada; 8Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 9Laboratorio de Psiquiatría Experimental, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, CDMX, MéxicoCorrespondence: Francisco Pellicer, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México Xochimilco 101, San Lorenzo Huipulco, Alcaldía Tlalpan, CDMX, 14370, México, Tel +52 55 41605063, Email pellicer@imp.edu.mxObjective: Pain constitutes an essential alarm for preserving the organism’s integrity. Damage to the nervous system produces a pathological condition known as neuropathic pain.Purpose: Blood oxygenation level-dependent (BOLD) and functional magnetic resonance imaging (fMRI) have been widely used to map neuroanatomy and the active regions of interest (ROI) of nociceptive processing. Our study explored the brain’s BOLD response in rats after thermal noxious stimulation, immediately after sciatic nerve damage and during 75 minutes after surgical lesion of the sciatic nerve.Methods: Nine male Wistar rats were tested; the experiments were performed on a 7-Tesla /21-cm Varian Agilent system. This approach allowed, for the first time, to measure in vivo the BOLD changes in brain regions involved with the pain process: cingulated (ACC), somatosensory (S1), and insular cortices (IC), as well as thalamus (Th) and ventral tegmental area (VTA) related with acute thermal pain and during the early stages of sciatic denervation that produce neuropathic pain.Results: During thermonociception scan, all subjects showed BOLD activation in the ROIs determined as ACC, S1, Th, IC and VTA. After denervation, these regions continued to show activation with a slow decrement in intensity for the duration of the experiment. The results suggest that these brain structures are overactive during the genesis of neuropathic pain.Conclusion: The study shows for the first time continuous activation of the pain matrix following an acute thermal nociceptive stimulus followed by neuropathic damage. These results have given insight into the early stages of the development of neuropathic pain in vivo.Keywords: fMRI, resting state, neuropathic pain, pain matrix, chronic pain, acute pain

Ulises Coffeen, Francisco Pellicer Research in Neurosciences, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City, México Abstract: Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties. Keywords: Salvia divinorum, salvinorin A, pain, inflammation, psychoactivity

Geospatial data catalogs enable users to discover and access geographical information. Prevailing solutions are document oriented and fragment the spatial continuum of the geospatial data into independent and disconnected resources described through metadata. Due to this, the complete answer for a query may be scattered across multiple resources, making its discovery and access more difficult. This paper proposes an improved information retrieval process for geospatial data catalogs that aggregates the search results by identifying the implicit spatial/thematic relations between the metadata records of the resources. These aggregations are constructed in such a way that they match better the user query than each resource individually. [ABSTRACT FROM PUBLISHER]

Objective: To assess the effect of a 2-week treatment with dexibuprofen, in comparison with ibuprofen and diclofenac, on pepsinogen plasma concentrations and gastrointestinal mucosa, as well as the correlation of these changes with gastrointestinal mucosal injury. Methods: 60 patients with rheumatologic disease in chronic therapy with NSAID, were included. After a 7-day rtm-in period patients were randomly assigned to receive a 14-day treatment with dexibuprofen (Group A; Day 1–3 = 400 mg t.i.d; Day 4–14 = 400 mg b.i.d.), ibuprofen (Group B; Day 1–3 = 800 mg t.i.d; Day 4–14 = 800 mg b.i.d.) or diclofenac (Group C; Day 1–3 = 50 mg t.i.d; Day 4–14 = 50 mg b.i.d.). Upper gastrointestinal endoscopy (Day 15), capsule-endoscopy (Day 16, 7 patients of each group) and determination of pepsinogen plasma concentrations were performed (basal and Day 15). A semiquantitative scale was designed for the assessment of the gastrointestinal mucosa. Results: No differences in plasma pepsinogen were found between treatment groups or gastrointestinal injury grades or between basal and post-therapy determinations. Dexibuprofen showed gastroduodenal and mucosal injury in fewer patients (42.1%) than was the case with ibuprofen (5%; p = 0.003) and diclofenac (30%; p = N.S.). Dexibuprofen administration was also associated with more patients having no intestinal mucosal damage (42.86% vs. 28.7% in the diclofenac group and 14.29% in the ibuprofen group; p = 0.0175). The rate of clinical adverse events was similar in Groups A, B and C (28%, 38% and 34%). Conclusions: Dexibuprofen showed a lower rate of gastroduodenal and intestinal mucosal injury. This effect was not mediated by modifications of plasma pepsinogen levels. [ABSTRACT FROM AUTHOR]

The role of nitric oxide as a neurotransmitter in the olfactory and chemoreception systems of invertebrates has been well documented. This suggests an early and efficient sensory detection system that is evolutionarily preserved in various species, including vertebrates and invertebrates. Additionally, the presence of a nitric oxide neurotransmitter system has been reported in molluscs, particularly in octopus species. In this work, we present evidence for the existence of nitric oxide synthase in neurons and fibers, as well as its anatomical localization in various nuclei involved in chemosensory integration and the motor responses associated with these processes in Octopus maya., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Pain is a morbidity or comorbidity with a high incidence that significantly impacts the well-being of patients. In this study, we evaluated the effects of systemic administration of tramadol, a weak mu-opioid receptor (MOR) agonist, plus quinpirole (a D2-like receptor agonist). The study was performed in naïve rats and in rats with induced inflammatory and neuropathic pain. To measure the antinociceptive effect of the drugs, thermonociceptive and mechanonociceptive stimuli were applied and the emotional aspects of pain were evaluated using conditional place preference (CPP) experiments. Systemic quinpirole produced an antinociceptive effect only in naïve male rats. In naïve female animals, a small but significant pronociceptive effect was observed following quinpirole application. Tramadol plus quinpirole in male animals reversed allodynia and hyperalgesia induced by inflammatory and neuropathic insults, which were not alleviated by either drug alone. CPP experiments revealed that systemic quinpirole plus tramadol treatment was effective only in an inflammatory pain model. To evaluate whether tolerance to the antinociceptive effect was prevented by the combination of the drugs, a repeated administration five-day trial of tramadol plus quinpirole was evaluated under inflammatory pain conditions; quinpirole only slightly prevented the antinociceptive tolerance of MOR agonists. D2-like agonists are effective adjuvants for treating painful conditions in combination with a low dose of MOR agonists. Our results could lead to an investigation of whether these dopaminergic drugs in combination with opioids might reduce the MOR agonist dose while obtaining a higher analgesic effect with fewer side effects in humans., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC.

Raphanus sativus L. cv. Sango, commonly known as red radish , is widely consumed around the world as a vegetable, but its benefit in pain relief is not sufficiently investigated. This study aimed to evaluate the antinociceptive effects of R. sativus and a possible mechanism of action. An aqueous extract of R. sativus sprouts (AERSS) was investigated by parenteral (10, 30, and 100 mg kg -1 , i.p.) and enteral (500 mg kg -1 , p.o.) administration in the neurogenic and inflammatory phases of the formalin test, where gastric damage was also evaluated as a possible adverse effect. Ketorolac (5 mg kg -1 , i.p.) was used as the reference drug. Endogenous opioid and 5-HT1A serotonin receptors, as well as the cAMP/NO-cGMP pathways, were explored in the study of a possible mechanism of action by using their corresponding antagonists: naloxone, 1 mg kg -1 , i.p., WAY100635, 1 mg kg -1 , i.p., and enzymatic activators or inhibitors, respectively. Sulforaphane (SFN), a known bioactive metabolite, was analyzed using electroencephalography (EEG) to evidence its central involvement. A significant and dose-dependent antinociceptive activity was observed with the AERSS resembling the antinociceptive effect of the reference drug, with an equivalent significant response with a dose of 500 mg kg -1 , p.o. without causing gastric damage. The participation of the endogenous opioid and 5-HT 1A serotonin receptors at central and peripheral levels was also observed, with a differential participation of cAMP/NO-cGMP. SFN as one metabolite produced significant changes in the EEG analysis, reinforcing its effects on the CNS. Our preclinical evidence supports the benefits of consuming Raphanus sativus cv. Sango sprouts for pain relief.

Natural products are recognized as potential analgesics since many of them are part of modern medicine to relieve pain without serious adverse effects. The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of an aqueous extract of Brassica oleracea var. italica sprouts (AEBS) and one of its main reported bioactive metabolites sulforaphane (SFN). Antinociceptive activity of the AEBS (30, 100, and 300 mg/kg, i.p. or 1000 and 2000 mg/kg, p.o.) and SFN (0.1 mg/kg, i.p.) was evaluated in the plantar test in rats to reinforce its analgesic-like activity at central level using the reference drug tramadol (TR, 50 mg/kg, i.p.). The anti-inflammatory-like response was determined in the carrageenan-induced oedema at the same dosages for comparison with ketorolac (KET, 20 mg/kg, i.p.) or indomethacin (INDO, 20 mg/kg, p.o.). A histological analysis of the swollen paw was included to complement the anti-inflammatory response. Additionally, acute toxicity observed in clinical analgesics as the most common adverse effects, such as sedation and/or gastric damage, was also explored. As a result, central and peripheral action of the AEBS was confirmed using enteral and parenteral administration, in which significant reduction of the nociceptive and inflammatory responses resembled the effects of TR, KET, or INDO, respectively, involving the presence of SFN. No adverse or toxic effects were observed in the presence of the AEBS or SFN. In conclusion, this study supports that Brassica oleracea var. italica sprouts are a potential source of antinociceptive natural products such as SFN for therapy of pain alone and associated to an inflammation condition., (© 2023. The Author(s).)

Salvia amarissima Ortega is an endemic species of Mexico used in folk medicine to alleviate pain and as a nervous tranquilizer. The S. amarissima extract and one of its abundant metabolites, identified and isolated through chromatographic techniques, were investigated to obtain scientific evidence of its potential effects to relieve nociplastic pain such as fibromyalgia. Then, the extract and amarisolide A (3-300 mg/kg, i.p.) were pharmacologically evaluated in reserpine-induced fibromyalgia-type chronic pain and in depressive-like behavior (as a common comorbidity) by using the forced swimming test in rats. The 5-HT 1A serotonin receptor (selective antagonist WAY100635, 1 mg/kg, i.p.) was explored after the prediction of a chemical interaction using in silico analysis to look for a possible mechanism of action of amarisolide A. Both the extract and amarisolide A produced significant and dose-dependent antihyperalgesic and antiallodynic effects in rats, as well as significant antidepressive behavior without sedative effects when the antinociceptive dosages were used. The 5-HT 1A serotonin receptor participation was predicted by the in silico descriptors and was corroborated in the presence of WAY100635. In conclusion, S. amarissima possesses antihyperalgesic, antiallodynic, and anti-depressive activities, partially due to the presence of amarisolide A, which involves the 5-HT 1A serotonin receptor. This pharmacological evidence suggests that S. amarissima and amarisolide A are both potential alternatives to relieve pain-like fibromyalgia.

Rationale: Exposure of male rats to an inaccessible receptive female and copulation increases dopamine (DA) levels in the nucleus accumbens (NAcc). Males copulating to satiety become sexually inhibited and most of them do not display sexual activity when presented with a sexually receptive female 24 h later. This inhibitory state can be pharmacologically reversed. There are no studies exploring NAcc DA levels during this sexual inhibitory state., Objectives: To characterize changes in NAcc DA and its metabolites' levels during sexual satiety development, during the well-established sexual inhibitory state 24 h later, and during its pharmacological reversal., Methods: Changes in NAcc DA and its metabolites were measured in sexually experienced male rats, using in vivo microdialysis, during copulation to satiety, when presented to a new sexually receptive female 24 h later, and during the pharmacological reversal of the sexual inhibition by anandamide., Results: NAcc DA levels remained increased during copulation to satiety. DA basal levels were significantly reduced 24 h after copulation to satiety, as compared to the initial basal levels. Presenting a receptive female behind a barrier 24 h after satiety did not induce the typical NAcc DA elevation in the sexually satiated males but there was a decrease that persisted when they got access to the female, with which they did not copulate. Anandamide injection slightly increased NAcc DA levels coinciding with sexual satiety reversal., Conclusions: Reduced NAcc DA concentrations coincide with the inhibition of an instinctive, natural rewarding behavior suggesting that there might be a DA concentration threshold needed to be responsive to a rewarding stimulus., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibromyalgia (FM) is a pain syndrome characterized by chronic widespread pain and CNS comorbidities. Tilia americana var. mexicana is a medicinal species used to treat anxiety, insomnia, and acute or chronic pain. However, its spectrum of analgesic efficacy for dysfunctional pain is unknown. To investigate a possible therapeutic alternative for FM-type pain, an aqueous Tilia extract (TE) and its flavonoid fraction (FF) containing rutin and isoquercitrin were evaluated alone and/or combined with clinical drugs (tramadol-TRA and pramipexol-PRA) using the reserpine-induced FM model in rats. Chromatographic analysis allowed the characterization of flavonoids, while a histological analysis confirmed their presence in the brain. TE (10-100 mg/kg, i.p.) and FF (10-300 mg/kg, i.p.) produced significant and dose-dependent antihyperalgesic and antiallodynic effects equivalent to TRA (3-10 mg/kg, i.p.) or PRA (0.01-1 mg/kg, s.c.). Nevertheless, the combination of FF + TRA or FF + PRA resulted in an antagonistic interaction by possible competitive action on the serotonin transporter or µ-opioid and D 2 receptors, respectively, according to the in silico analysis. Flavonoids were identified in cerebral regions because of their self-epifluorescence. In conclusion, Tilia possesses potential properties to relieve FM-type pain. However, the consumption of this plant or flavonoids such as quercetin derivatives in combination with analgesic drugs might reduce their individual benefits.

The search for molecules that contribute to the relief of pain is a field of research in constant development. Lamiaceae is one of the most recognized families world-wide for its use in traditional medicine to treat diseases that include pain and inflammation. Mexico can be considered one of the most important centers of diversification, and due to the high endemism of this family, it is crucial for the in situ conservation of this family. Information about the most common genera and species found in this country and their uses in folk medicine are scarcely reported in the literature. After an extensive inspection in bibliographic databases, mainly Sciencedirect, Pubmed and Springer, almost 1200 articles describing aspects of Lamiaceae were found; however, 217 articles were selected because they recognize the Mexican genera and species with antinociceptive and/or anti-inflammatory potential to relieve pain, such as Salvia and Agastache . The bioactive constituents of these genera were mainly terpenes (volatile and non-volatile) and phenolic compounds such as flavonoids (glycosides and aglycone). The aim of this review is to analyze important aspects of Mexican genera of Lamiaceae, scarcely explored as a potential source of secondary metabolites responsible for the analgesic and anti-inflammatory properties of these species. In addition, we point out the possible mechanisms of action involved and the modulatory pathways investigated in different experimental models. As a result of this review, it is important to mention that scarce information has been reported regarding species of this family from Mexican genera. In fact, despite Calosphace being one of the largest subgenera of Salvia in the world, found mainly in Mexico, it has been barely investigated regarding its potential biological activities and recognized bioactive constituents. The scientific evidence regarding the different bioactive constituents found in species of Lamiaceae demonstrates that several species require further investigation in preclinical studies, and of course also in controlled clinical trials evaluating the efficacy and safety of these natural products to support their therapeutic potential in pain relief and/or inflammation, among other health conditions. Since Mexico is one of the most important centers of diversification, and due to the high endemism of species of this family, it is crucial their rescue, in situ conservation, and investigation of their health benefits.

Maqui-berry is characterised by presenting a high concentration of (poly)phenols, accounting anthocyanins (cyanidin and delphinidin) for over 85% of the total. These coloured flavonoids have demonstrated potential neurological activity, but the evidence of their antinociceptive properties is scarce. In order to cover this gap, different doses (suitable for human administration) of a maqui-berry powder (1.6% anthocyanin), using enteral and parenteral routes of administration, were compared at central and peripheral levels using a nociceptive pain model (formalin test) in mice. Gastric damage analysis as possible adverse effects of analgesic and anti-inflammatory drugs was also explored. Dose-antinociceptive response was confirmed using both routes of administration and in both neurogenic and inflammatory phases of the formalin test, without gastric damage. In conclusion, these preliminary data provide evidence of pharmacological properties of maqui-berry to alleviate nociceptive pain.

Pain by chemical irritants is one of the less well-described aspects of nociception. The acidic substance is the paradigm of the chemical noxious compound. An acidic insult on cutaneous, subcutaneous and muscle tissue results in pain sensation. Acid (or H + ) has at least two main receptor channels in dorsal root ganglia (DRG) nociceptors: the heat receptor transient receptor potential vanilloid 1 (TRPV1) and the acid-sensing ionic channels (ASICs). TRPV1 is a low-sensitivity H + receptor, whereas ASIC channels display a higher H + sensitivity of at least one order of magnitude. In this review, we first describe the functional and structural characteristics of these and other H + -receptor candidates and the biophysics of their responses to low pH. Additionally, we compile reports of the expression of these H + -receptors (and other possible complementary proteins) within the DRG and compare these data with mRNA expression profiles from single-cell sequencing datasets for ASIC3, ASIC1, transient receptor potential Ankiryn subtype 1 (TRPA1) and TRPV1. We show that few nociceptor subpopulations (discriminated by unbiased classifications) combine acid-sensitive channels. This comparative review is presented in light of the accumulating evidence for labeled-line coding for most noxious sensory stimuli., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Páez, Segura-Chama, Almanza, Pellicer and Mercado.)

Although physiologically pain has a protective function, in many diseases, it is one of the most prominent symptoms. Today, new trends are focused on finding more natural alternatives to conventional treatments to alleviate it. Thereby, the purpose of this investigation was to obtain preclinical data of the antinociceptive properties of a lyophilized obtained from a newly designed maqui-citrus beverage alone and added with different sweeteners. To achieve this objective, maqui berry and citrus pharmacological activity were studied separately, as well as the interaction of both ingredients. In addition, due to the controversy generated regarding the intake of sugars, related to different metabolic diseases, the influence of different sweeteners (stevia, sucralose, or sucrose) was studied to determine their possible influence on the bioactive compounds of this product. For the attainment of our goals, a pharmacological evaluation, using the 1% formalin test, a nociceptive pain model in mice, was performed by using a sub-efficacious dosage of Maqui (25 mg/kg, i.p.) alone and combined with citrus, and then compared with the effects obtained in the presence of the different sweeteners. As a result, the antinociceptive response of the maqui was synergized in the presence of citrus in the neurogenic and inflammatory phases of the formalin test. However, this response was partially or totally reduced in the presence of the sweeteners. Our study gives preclinical evidence that a combination of maqui and citrus might exert beneficial actions to relieve pain, whereas the presence of sweeteners could reduce or avoid it.

Nociceptive stimuli attributes are codified in the periphery; at this level, D2-like dopamine (DA) receptor activation decreases the high voltage-gated Ca 2+ current predominantly in mechanonociceptive neurons, which explains the presynaptic action mechanism of the antinociception produced by quinpirole when it is intrathecally administered in rats. However, the identity of D2-like DA receptor subtype that mediates this effect remains unknown. To answer this question, we used Fluo-4-based Ca 2+ microfluorometry to study the depolarization-elicited [Ca 2+ ] i increase in small non-peptidergic DRG neurons (identified by its binding to the Isolectin B 4 ), and to test the effect of D2-like DA receptor activation by quinpirole in presence of selective antagonists for D2, D3, and D4 DA receptors. The results showed a significantly greater contribution of the D4 DA receptor in the down-modulation of depolarization-elicited [Ca 2+ ] i increase in small non-peptidergic DRG neurons compared to the other receptors. Although the D2 and D3 receptor antagonists also slightly inhibited the effect of quinpirole, their effects were significantly weaker than those of the D4 receptor antagonist. Furthermore, we showed that quinpirole selectively inhibits the Ca V 2.2 Ca 2+ channels. Our results suggest that the activation of the D4 DA receptors is a promising strategy for pain management at the spinal cord level., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been reported that environmental stimuli can positively influence addictive responses and the pharmacological effects of drugs of abuse. In this work, we evaluated the ability of environmental enrichment (EE) to attenuate addictive behaviours in mice after repeated exposure to toluene. We also analysed the role of D1 receptors (D1R) in animals chronically exposed to toluene and in those housed under EE. Mice (Swiss Webster) were exposed to toluene (0, 2000 or 4000 ppm, 30 min a day), and addictive responses were examined in the behavioural sensitization model. The induction of sensitization was evaluated over 4 weeks, and its expression was assessed in animals repeatedly exposed to toluene (0 or 4000 ppm, 30 min a day/4 weeks) and then housed under EE conditions during 4 more weeks. D1R levels were measured under these two experimental conditions in the prefrontal cortex, nucleus accumbens, hippocampus and caudate. The results showed that D1R levels decreased during toluene-induced behavioural sensitization. An increase in D1R levels was found in animals housed in EE conditions, in addition to the attenuated expression of behavioural sensitization. These results indicate that environmental stimulation attenuates addictive behaviour induced by toluene and that dynamic changes in D1R are linked in this response., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Salvia divinorum Epling & Játiva is a Mexican plant used not only in rituals but also in traditional medicine for pain relief. One of the most known bioactive compounds is salvinorin A, which acts centrally in kappa-type opioid receptors., Aim of the Study: Despite its traditional use as a medicinal plant, there is not enough scientific investigation to reinforce its potential as analgesic. In this study, Salvia divinorum antinociceptive activity was evaluated in experimental models of nociceptive pain; the writhing test and formalin-induced licking behavior in mice., Material and Methods: Different Salvia divinorum extracts were prepared by maceration at room temperature in increased polarity (hexane, ethyl acetate and methanol). The ethyl acetate extract (EAEx) was chosen in order to be fractioned and to obtain a mixture of salvinorins. The antinociceptive effect of EAEx (3, 10, 30, and 100 mg/kg, i.p.) was compared with that of tramadol (a partial opioid agonist analgesic drug, 30 mg/kg, i.p.) and the mixture of salvinorins (30 mg/kg, i.p.). In addition, a participation of opioids (naloxone, NX 1 and/or 3 mg/kg, i.p.) and serotonin 5-HT 1A receptors (WAY100635, 0.32 mg/kg, i.p.) was investigated as possible inhibitory neurotransmission involved., Results: As a result, the EAEx produced significant and dose-dependent antinociceptive effect concerning salvinorins constituents. This effect was blocked in the presence of NX and WAY100635 in the abdominal test, but only by NX in the formalin-induced licking behavior. Whereas, the effect of salvinorins mixture involved opioids and serotonin 5-HT 1A receptors., Conclusion: Data provide evidence of the potential of this species, where salvinorin A is in part responsible bioactive constituent involving participation of the opioids and/or 5-HT 1A serotonin receptors depending on the kind of pain model explored., (Copyright © 2019. Published by Elsevier B.V.)

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca 2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB 4 + (nonpeptidergic) and IB 4 - (peptidergic). Intracellular [Ca 2+ ] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca 2+ influx and inhibited the high voltage-activated Ca 2+ current (HVA-I Ca ) in half of IB 4 + neurons, leaving Ca 2+ entry and HVA-I Ca in IB 4 - neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-I Ca from IB 4 + neurons, indicating that quinpirole mainly inhibits Ca V 2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB 4 + small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Tagetes lucida Cav. is an ancient medicinal plant used to treat different ailments involving neurological diseases and pain. However, scientific studies to validate their medicinal properties as analgesic have not been described. The aim of this study was to evaluate the T. lucida antinociceptive response using pain models. Bioactive compounds and a possible mechanism of action were also explored. Dose-response effects of an ethanol crude extract were investigated in the writhing and formalin tests in mice and rats, respectively. The extract was fractionated to isolate active fractions and bioactive compounds (quercetagetin 7‑O‑β‑d‑glucoside and 6,7‑dimethoxycoumarin) using the formalin test. The antinociceptive effects were compared to the reference drugs (tramadol 10 mg/kg, diclofenac 50 mg/kg, and/or ketorolac 1 mg/kg, i.p.). The ethanol extract was explored in the presence of naloxone (3 mg/kg, i.p. a non-selective opioid receptor antagonist) and WAY100635 (0.5 mg/kg, s.c., a selective 5-HT 1A receptor antagonist) to screen their participation as possible inhibitory mechanisms involved in the antinociceptive response of T. lucida. The ethanol crude extract, fractions, and pure compounds caused a significant antinociceptive response resembling the effect of the reference drugs. Both opioid and 5-HT 1A receptors participated in the analgesic -like activity of the extract, which did not produce gastric damage. On the contrary, the gastric damage produced as an adverse effect of the analgesic ketorolac was prevented when combined with the extract. In conclusion, these preliminary data provide evidence and give support to the properties attributed to T. lucida in the traditional medicine to alleviate pain., (Copyright © 2019. Published by Elsevier Inc.)

Opioids are potent analgesic drugs, but their use has been limited due to their side effects. Antinociceptive effects of D2-like receptor agonists such as quinpirole have been shown at the spinal cord level; however, their efficacy is not as high as that of opioids. Dopaminergic agonists are long-prescribed and well-tolerated drugs that have been useful to treat clinically and experimentally painful conditions. Because current pain treatments are not completely effective, the aim of this work was to determine if a D2-like receptor agonist improves the antinociceptive effects of a μ-opioid receptor agonist. Drugs were intrathecally administered in adult rats; mechanonociceptive and thermonociceptive tests were carried out. Intraplantar injection of complete Freund's adjuvant (CFA) and sciatic loose ligation (SLL) were used for inflammatory and neuropathic models of pain, respectively. In intact animals, D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; a µ-opioid receptor agonist) increased the paw withdrawal latencies (PWL) in thermal and mechanical nociceptive tests in a dose-dependent manner. Quinpirole (D2-like receptor agonist) increased PWL only in mechanonociception. In the presence of quinpirole (1 nmol), the ED 50 of the mechanical antinociceptive effect of DAMGO was significantly decreased (8-fold). Coadministration of 1 nmol quinpirole and 30 pmol DAMGO completely reversed hyperalgesia in the CFA model, whereas 100 pmol DAMGO plus 1 nmol quinpirole reversed the allodynia in the SLL model. This work offers evidence about a synergistic antinociceptive effect between opioidergic and dopaminergic drugs. This combination may relieve painful conditions resistant to conventional treatments, and it may reduce the adverse effects of chronic opioid administration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome with various concomitant symptoms like sleep disorders. FM patients are mainly women and menopause might play an important role in the altered processing of somatosensory information. Adverse effects and moderated efficacy of drugs promote treatment discontinuation by patients. Animal models of FM report pain and depression-like behaviors, but none of them have explored sleep disturbance as possible marker in the preclinic diagnostic. The aim of this study was to investigate alterations of the sleep architecture in the reserpine (RES)-induced FM model in ovarectomized (OVX) rats. The behavioral thresholds of nociceptive response in the experimental FM were analyzed in a first block using muscle pressure, tactile response and allodynia to cold stimulus. In a second block, the sleep-wake cycle was examined in a polysomnographic study. Groups (n = 8) consisted in: (a) no treatment, (b) RES vehicle, (c) RES alone, (d) RES + vehicle of fluoxetine (FLX, antidepressant reference drug), and (e) RES + FLX. Our results demonstrated that RES induced pain-related behavior (50-70%) in OVX rats and altered sleep architecture by the increase of total wake time (38%), diminution of the no-REM stage (SWS-I 33% and SWS-II 76%), and abolition of the REM sleep, effects that were partially reverted in the presence of FLX. In conclusion, our results support the face validity of the RES-induced pain-related behavior as FM model showing nociceptive behavioral responses associated to sleep alterations observed as symptoms in FM patients; thus, these evidences substantiate its usefulness to look for alternatives of treatment for FM symptoms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Borderline personality disorder (BPD) is a chronic condition characterized by high levels of impulsivity, affective instability, and difficulty to establish and manage interpersonal relationships. However, little is known about its etiology and neurobiological substrates. In our study, we wanted to investigate the influence of child abuse in the psychopathology of BPD by means of social cognitive paradigms [the Movie for the Assessment of Social Cognition (MASC) and the reading the mind in the eyes test (RMET)], and resting state functional magnetic resonance imaging (rs-fMRI). For this, we recruited 33 participants, 18 BPD patients, and 15 controls. High levels of self-reported childhood maltreatment were reported by BPD patients. For the sexual abuse subdimension, there were no differences between the BPD and the control groups, but there was a negative correlation between MASC scores and total childhood maltreatment levels, as well as between physical abuse, physical negligence, and MASC. Both groups showed that the higher the level of childhood maltreatment, the lower the performance on the MASC social cognitive test. Further, in the BPD group, there was hypoconnectivity between the structures responsible for emotion regulation and social cognitive responses that have been described as part of the frontolimbic circuitry (i.e., amygdala). Differential levels of connectivity, associated with different types and levels of abuse were also observed.

Previous comparative research on the evolution of cognition has tested what we call the "altricial intelligence hypothesis". This posits that a relationship between evolutionary changes in the altricial period length and cognition exists across animal species. However, the evidence available thus far either comes from indirect measurements of cognition or has not been conclusive. We performed a phylogenetic analysis of published data from various sources on 31 homeothermic species to test for an evolutionary association between the degree of altriciality and a direct measure of self-control. For each species, the degree of altriciality was determined based on the residual altricial period (i.e., the time from birth to fledging in birds and to weaning in mammals) on lifespan. The percentage of success in the cylinder task was the measure of self-control. Our results showed that the degree of altriciality covaried positively with the measure of self-control. Based on the results of this study, we sustain that evolutionary changes in the length of the altricial period are associated with evolutionary changes in the cognitive system used by homeotherms to perform the cylinder task., Competing Interests: The authors have declared that no competing interests exist.

Objective: Current treatment of borderline personality disorder (BPD) consists of psychotherapy and pharmacological interventions. However, the use of repetitive transcranial magnetic stimulation (rTMS) could be beneficial to improve some BPD symptoms. The objective of this study was to evaluate clinical improvement in patients with BPD after application of rTMS over the right or left dorsolateral prefrontal cortex (DLPFC)., Method: Twenty-nine patients with BPD from the National Institute of Psychiatry, Mexico, were randomized in two groups to receive 15 sessions of rTMS applied over the right (1 Hz, n=15) or left (5 Hz, n=14) DLPFC. Improvement was measured by the Clinical Global Impression Scale for BPD (CGI-BPD), Borderline Evaluation of Severity Over Time (BEST), Beck Depression Inventory (BDI), Hamilton Anxiety Rating Scale (HAM-A), and Barratt Impulsiveness Scale (BIS)., Results: Intragroup comparison showed significant (p < 0.05) reductions in every psychopathologic domain of the CGI-BPD and in the total scores of all scales in both groups., Conclusions: Both protocols produced global improvement in severity and symptoms of BPD, particularly in impulsiveness, affective instability, and anger. Further studies are warranted to explore the therapeutic effect of rTMS in BPD., Clinical Trial Registration: NCT02273674

Flavonoids are natural compounds showing anti-hyperalgesic activity in models of pain. Diosmin is a compound poorly studied in the treatment of neuropathic pain. This study evaluates the anti-hyperalgesic actions of diosmin and possible mechanisms of action involved by using a neuropathic pain model in rats. Experimental neuropathic pain was induced by chronic constriction injury (CCI) in male Wistar rats, then aesthesiometric index and plantar tests were assessed to evaluate mechanical and thermal hyperalgesia, respectively, in order to explore the analgesic effects of acute and sub-chronic treatment with diosmin. The GABA A , 5-HT 1A , D 2 -like and opioid receptors participation, as well as levels of TNF-α, IL-1β and IL-6, were evaluated in the spinal cord and sciatic nerve tissues after acute and subchronic diosmin administration. In addition, the presence of diosmin on cerebral samples was determined by UHPLC-MS analysis. Acute and sub-chronic treatment with diosmin significantly diminished the mechanical and thermal hyperalgesia induced by CCI in rats. This anti-hyperalgesic effects of diosmin were modified in the presence of naloxone (1mg/kg, i.p.) and haloperidol (0.1mg/kg, i.p.), but not by GABA A and 5-HT 1A receptor antagonists. The anti-hyperalgesic effects of diosmin were also linked with reduced levels of TNF-α, IL-1β and IL-6. The presence of diosmin in the cerebral samples was confirmed by chromatographic analysis. In conclusion, our results provide evidence that diosmin produces significant anti-hyperalgesic effects acting at central level by an opioid and D 2 dopaminergic receptors participation, and at peripheral level by reducing proinflammatory cytokines., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists., Aim of the Study: Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans., Material and Methods: Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects., Results: Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes., Conclusion: The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Broccoli is a rich source of health-promoting glucosinolates, phenolic compounds, minerals and vitamins, which might have potential to alleviate pain., Aim: To explore the antinociceptive effects of a broccoli sprout aqueous extract (BSE) in experimental models of pain and an opioid mechanism., Materials and Methods: the BSE was administered to mice and rats that were subjected to the writhing and formalin tests, respectively. Gastric damage or sedative-like response, as adverse effects observed in anti-inflammatory non-steroidal and opioid analgesic drugs, respectively, were also explored., Results: Antinociception, but not sedative or gastric injury response, was observed in a significant and dose-dependent manner with the BSE (50-500 mg kg -1 , i.p. and 500-2000 mg kg -1 , p.o.) in comparison to the control group; these effects resembled those observed with the analgesic tramadol (30 mg kg -1 , i.p.) in writhing and formalin assessments. Blockage of opioid receptors by naloxone (1 mg kg -1 , i.p.) produced partial inhibition of the antinociceptive effect of the BSE in both assays., Conclusion: This study gives evidence of the potential activity of broccoli sprouts in pain therapy.