Search Results (232)

Migraine is a neurovascular paroxysmal disorder characterized by neurogenic inflammation and has a remarkable impact on the quality of life. The Food and Drug Administration (FDA) approved onabotulinumtoxin A in 2010 for the prophylactic treatment of chronic migraine. Today, in its 4th decade, it is approved in 100 countries for 15 main indications. Its mechanism of action, based on the inhibition of neurotransmitter release from primary sensory neurons, is very complex: it affords antinociception, but it also has an analgesic effect on neuropathic pain conditions and reduces the need for rescue medications. Genetic variants have been investigated for their potential role in the pathogenesis and clinical expression of migraine and of the response to treatments. These studies primarily involved genes associated with vascular regulation and cardiovascular pathology, including those encoding angiotensin-converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR). However, epigenetics and, particularly, genetic and epigenetic modifications are still poorly studied in terms of understanding the mechanisms implicated in susceptibility to migraine, aura, chronification and response to symptomatic and preventive treatments. In particular, the aim of the present study is to gather evidence on the genetic variants and epigenetic modifications affecting the pathway of the calcitonin gene-related peptide (CGRP), the target of onabotulinumtoxin A and of all the novel monoclonal antibodies. Full article

Pain is a protective mechanism that can be classified into acute and chronic types. Ayahuasca is a psychoactive brew rich in dimethyltryptamine or DMT (a 5-HT_2A receptor agonist), and harmine (a monoamine-oxidase (MAO) inhibitor) used for religious and therapeutic purposes. Previous preclinical and anecdotal evidence suggests that ayahuasca and its compounds have antinociceptive and anti-inflammatory effects due to 5-HT_2A agonism and MAO inhibition. Thus, the current study aims to provide a systematic review of the antinociceptive and anti-inflammatory effects of ayahuasca and its alkaloids in preclinical models. All studies published up to December 2024 were screened and evaluated for eligibility. A total of 1535 publications were identified, of which 29 adhered to the predefined criteria. Reviewed articles reported antinociceptive effects of ayahuasca, harmine, and harmaline. Regarding anti-inflammatory effects, the compounds of ayahuasca, especially harmine, have demonstrated a reduction and an increase in pro-inflammatory and anti-inflammatory cytokines, respectively. Although there are promising results regarding the antinociceptive and anti-inflammatory effects of ayahuasca and its alkaloids, further investigation is needed. Full article

Celtis iguanaea, widely used in Brazilian folk medicine, is known for its analgesic and anti-inflammatory properties. This study evaluated the in vitro antioxidant capacity and the in vivo antinociceptive and anti-inflammatory mechanisms of the standardized spray-dried Celtis iguanaea hydroethanolic leaf extract (SDCi). Phytochemical analysis showed that SDCi contains 21.78 ± 0.82 mg/g polyphenols, 49.69 ± 0.57 mg/g flavonoids, and 518.81 ± 18.02 mg/g phytosterols. UFLC-DAD-MS identified iridoid glycosides, p-coumaric acid glycosides, flavones, and unsaturated fatty acids. Antioxidant assays revealed an IC₅₀ of 301.6 ± 38.8 µg/mL for DPPH scavenging and an electrochemical index of 6.1 μA/V. In vivo, SDCi (100–1000 mg/kg, p.o) did not impair locomotor function (rotarod test) but significantly reduced acetic acid-induced abdominal writhing and both phases of the formalin test at higher doses (300 and 1000 mg/kg). The antinociceptive effects were independent of α-2 adrenergic receptors. SDCi also increased latency in the hot-plate test and reduced paw edema in the carrageenan model, accompanied by decreased IL-1β and increased IL-10 levels. Histological analysis showed a 50% reduction in inflammatory cell infiltration. These findings support SDCi as an effective anti-inflammatory and antinociceptive phytopharmaceutical intermediate, with potential applications in managing pain and inflammation. Full article

Species belonging to the genus Cnidoscolus have been widely recognized for their diverse applications, including forage, oil production, latex, ornamental purposes, medicinal uses, and as nutritional sources. This study aimed to compile up-to-date information on the chemical, nutritional, and ethnopharmacological aspects, as well as the biological activities, of Cnidoscolus species, offering a critical overview of the current advancements in research on these plants. The reviewed literature indicates that Cnidoscolus species hold significant traditional use value, particularly in the treatment of conditions such as cancer, diabetes, and disorders affecting the uterus, prostate, ovaries, and kidneys, in addition to menstrual disturbances, inflammation, and general pain. Scientifically, their efficacy has been demonstrated in several contexts, including antinociceptive, antibacterial, anti-inflammatory, cytotoxic, antiproliferative, hypoglycemic, and antioxidant activities, among others. Additionally, certain species like C. aconitifolius have shown potential for human consumption, with leaves being eaten raw or cooked, while C. quercifolius demonstrates nutritional value in its seeds, which can be utilized in the development of functional foods. However, further studies are needed to focus on the isolation and characterization of bioactive compounds found in these species, as well as deeper investigations into the molecular and cellular mechanisms underlying their biological activities and assessments of the safety of long-term consumption in both humans and animals. Moreover, more extensive clinical and preclinical studies are essential to validate the proposed therapeutic effects and to support the safe and effective inclusion of these species in conventional treatment regimens. Full article

Affinin (spilanthol) is the main bioactive alkylamide present in Heliopsis longipes roots, exerting antinociceptive and anti-inflammatory effects that involve the activation of TRP channels. Previous studies indicated that affinin reduces the LPS-induced increase in pro-inflammatory cytokine production in murine macrophages. However, no studies have evaluated whether affinin produces antinociceptive, anti-inflammatory, and behavioral effects in experimental animals treated with LPS, nor has the mechanism of action involved in these pharmacological effects been established. The present study evaluated whether affinin induces hypothermia, catalepsy, hypolocomotion, and analgesia and, moreover, whether the analgesia involves the activation of the CB1 cannabinoid receptor and TRPV1 and TRPA1 channels. Subsequently, the anti-inflammatory activity and behavioral effects induced by affinin (20 mg/kg) in mice were evaluated via LPS (2.5 mg/kg)-induced hypothermia. The results of the experiments indicate that the analgesic effect of affinin involves the activation of the CB1 cannabinoid receptors and the TRPV1 and TRPA1 channels. Additionally, affinin reduced the severity of LPS-induced hypothermia and attenuated the increase in TNF-α and IL-6 levels in serum. The results obtained demonstrate that affinin induces antinociceptive, anti-hypothermic, and anti-inflammatory activities, which involve the CB1 receptor and the TRPV1 and TRPA1 channels and the suppression of pro-inflammatory cytokines. Full article

Background/Objectives: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and synthesis of a novel series of CBD-based structural analogues, and the in vivo evaluation of their potential antinociceptive activity. Methods: Using a two-step synthetic route, 26 new terpene-cinnamoyl acyl-hydrazone analogues were obtained and were submitted to in vivo screening in the classical formalin-induced paw edema and hot plate assays. Results: The compounds PQM-292, PQM-293, PQM-295, PQM-307, PQM-308, and PQM-309 exhibited the best results in the neurogenic phase (first phase) of the formalin-induced licking response, showing comparable results to morphine. Notably, in the inflammatory phase (second phase), compound PQM-292 exhibited the best anti-inflammatory activity. Interestingly, in the hot plate model, six other compounds (PQM-274, PQM-291, PQM-294, PQM-304, PQM-305, and PQM-378) showed the best antinociceptive activity in comparison to morphine, especially PQM-274, which exhibited an antinociceptive effect almost equivalent to the reference drug. Interestingly, these findings suggested that these bioactive compounds, despite their structural similarity, act through different mechanisms, which were investigated by molecular docking with CB1, CB2, and TRPV1 receptors. In silico results indicated that the most active compounds should act through different mechanisms, probably involving interactions with TRPA1. Conclusions: Therefore, due to the promising antinociceptive activity observed for these highlighted compounds, particularly for PQM-292 and PQM-274, without apparent toxicity and psychoactive effects, and the possible involvement of diverse mechanisms of action, these compounds could be considered as promising starting points to the development of new drug candidate prototypes of clinical interest. Full article

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K⁺ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K⁺ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K⁺ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K⁺ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K⁺ channel blockers), and apamin and charybdotoxin (Ca²⁺-activated K⁺ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K⁺ channel pathway. Full article

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment. Full article

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator of nervous system functions and plays a key role in neuronal growth and survival, neurotransmission, and synaptic plasticity. The effects of BDNF are mainly mediated by the activation of tropomyosin receptor kinase B (TrkB), expressed in both the peripheral and central nervous system. BDNF has been implicated in several neuropsychiatric conditions such as schizophrenia and anxio-depressive disorders, as well as in pain states. This review summarizes the evidence for a critical role of BDNF throughout the pain system and describes contrasting findings of its pro- and anti-nociceptive effects. Different cellular sources of BDNF, its influence on neuroimmune signaling in pain conditions, and its effects in different cell types and regions are described. These and endogenous BDNF levels, downstream signaling mechanisms, route of administration, and approaches to manipulate BDNF functions could explain the bidirectional effects in pain plasticity and pain modulation. Finally, current knowledge gaps concerning BDNF signaling in pain are discussed, including sex- and pathway-specific differences. Full article

Betalains are natural, hydrophilic pigments present in a variety of plants from the order Caryophyllales, extensively used as non-toxic food colorants and antioxidants. In recent decades, betalains have been intensively researched, with numerous studies confirming their anti-inflammatory, antioxidant, antimicrobial, and antinociceptive properties. More recently, due to a significant increase in the aging population worldwide, there has been growing interest in the study of preventive effects of betalains on age-related, degenerative brain diseases. The aim of this review is to evaluate the potential neuroprotective role of betalains in the prevention of neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, as well as other types of neurodegenerative and ischemic brain injuries. Preclinical in vivo and in vitro pharmacological studies investigating the neuroprotective effects of betalains are reviewed, with a focus on the putative mechanisms of action. Available studies in humans are also presented. Full article

Chronic pain significantly impacts quality of life and is often accompanied by inflammation, a natural bodily response that can become harmful when excessive. The orofacial region is commonly affected, making effective treatment crucial. However, current drugs often cause undesirable side effects, highlighting the need for new pharmacological alternatives. 4-hydroxycoumarin (4-HC), a natural compound, has shown promising antinociceptive and anti-inflammatory effects, but studies confirming its specific properties are limited. In silico analyses suggest that 4-HC exhibits favorable pharmacokinetic characteristics, not interacting with P-glycoprotein and successfully crossing the blood–brain barrier. Molecular docking studies indicate that its effects may be mediated through NMDA_R or by inhibiting iNOS. Our study assessed the antinociceptive and anti-inflammatory effects of 4-HC in animal models at doses of 25, 50, and 75 mg/kg. 4-HC significantly reduced abdominal contortions induced by acetic acid and decreased nociceptive rubbing in orofacial pain models induced by formalin, glutamate, and capsaicin. Interactions with opioid receptors were not observed, suggesting that 4-HC’s antinociceptive effect does not involve this pathway. Additionally, 4-HC reduced paw edema induced by carrageenan and significantly decreased leukocyte migration and TNF-α levels. These findings highlight the therapeutic potential of 4-HC and warrant further investigation into its mechanisms. Full article

Neuropathic pain (NP) is a type of chronic pain resulting from injury or dysfunction of the nerves or spinal cord. Previous studies have shown that the combination of ligustrazine (LGZ) and sinomenine (SIN) exerts a synergistic antinociceptive effect in peripheral and central NP models. On this basis, a comprehensive analgesic evaluation was performed in a chronic constriction injury (CCI)-induced NP model in rats. Sciatic nerve histopathological changes were observed, and 22 cytokines and chemokines levels were analyzed. We also combined network pharmacology and metabolomics to explore their molecular mechanisms. Results showed that the combination of LGZ and SIN significantly alleviated the pain-like behaviors in CCI rats in a time- and dose-dependent manner, demonstrating superior therapeutic effects compared to LGZ or SIN alone. It also improved pathological damage to sciatic nerves and regulated inflammatory cytokine levels. Network pharmacology identified shared and distinct pain-related targets for LGZ and SIN, while metabolomics revealed 54 differential metabolites in plasma, and 17 differential metabolites in CSF were associated with the combined intervention of LGZ and SIN. Finally, through an integrated analysis of the core targets and differential metabolites, tyrosine metabolism, phenylalanine metabolism, and arginine and proline metabolism were identified as potential key metabolic pathways underlying the therapeutic effects of LGZ and SIN in CCI treatment. In conclusion, our study provides evidence to support the clinical application of LGZ and SIN in the treatment of NP. Full article

The existing literature offers limited experimental evidence on the role of botulinum neurotoxin type E (BoNT-E) in pain transmission. The present study investigated the antinociceptive effects of subcutaneously administered BoNT-E in chronic orofacial pain conditions. This study used orofacial formalin-induced pronociceptive behavior and complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia as inflammatory pain models in male Sprague Dawley rats. A neuropathic pain model was also developed by causing an injury to the inferior alveolar nerve. Subcutaneously administered BoNT-E (6, 10 units/kg) significantly reduced nociceptive behavior during the second phase of the formalin test compared to that of the vehicle treatment. These doses similarly alleviated thermal hypersensitivity in the CFA-treated rats. Moreover, BoNT-E (6, 10 units/kg) markedly attenuated mechanical allodynia in rats with an inferior alveolar nerve injury. At a dose of 10 units/kg, BoNT-E produced antinociceptive effects that became evident 8 h post-injection and persisted for 48 h. Notably, BoNT-E (10 units/kg) significantly reduced the number of c-fos-immunostained neurons in the trigeminal subnucleus caudalis of rats with an inferior alveolar nerve injury. In comparison, intraperitoneally administered gabapentin (30, 100 mg/kg) demonstrated significant mechanical anti-allodynic effects but exhibited lower analgesic efficacy than that of BoNT-E. These findings highlight the potential of BoNT-E as a therapeutic agent for chronic pain management. Full article

Background/Objectives: Sesame (Sesamum indicum L.) is used in folk medicine to treat painful disorders. Sesamin is the main lignan found in this plant; however, its antinociceptive potential has scarcely been studied. The aim was to investigate the antinociceptive effect of sesamin on inflammatory and neuropathic pain models, as well as the possible mechanism of action through which sesamin mediates its own antinociceptive effect. Methods: Formalin and carrageenan animal models were used to assess inflammatory pain, whereas an L5/L6-spinal-nerve-ligated rat model was employed to evaluate neuropathic pain. Results: Oral sesamin significantly reduced carrageenan-induced hyperalgesia and inflammation, formalin-induced nociception, and L5/L6-spinal-nerve-ligation-induced allodynia. Sesamin was more effective than diclofenac in the inflammatory pain models, but it was less effective than pregabalin in the neuropathic pain model. The antinociceptive effect of sesamin, in the formalin test, was prevented by the intraperitoneal administration of methiothepin (5-HT_1/5 antagonist), but not by naltrexone (an opioid antagonist) or L-NAME (an NOS inhibitor). In addition, WAY-100635 (5-HT_1A antagonist), but not SB-224289 (5-HT_1B antagonist), BRL-15542 (5-HT_1D antagonist), and SB-699551 (5-HT_5A antagonist), impeded sesamin-induced antinociception. Conclusions: This study’s results support the use of sesamin to treat inflammatory pain disorders and suggest that 5-HT_1A receptors influence the antinociceptive effect of this drug. Full article

Background: Neuropathic pain can be triggered by chemotherapy drugs such as paclitaxel (PTX). Management of pain is limited by drugs’ ineffectiveness and adverse effects. Isopulegol (ISO) is a monoterpene present in the essential oils of several aromatic plants and has promising pharmacological activities. Objectives: to evaluate the antinociceptive activity of ISO in a PTX-induced neuropathic pain model. Methods: the toxicity of ISO was evaluated in healthy and cancerous cells. Behavioral assessments were performed using the von Frey and acetone tests. We investigated the involvement of the GABAergic pathway, NMDA, TNF-α, and the release of GABA and glutamate in the presence of ISO. Results: ISO showed little or no cytotoxicity in U87 and MDA-MB-231 cells. In both acute and subacute treatment, ISO at doses of 25, 50, and 100 mg/kg (* p < 0.05) increased the mechanical nociceptive threshold of neuropathic animals compared to the control group and reduced thermal sensitivity. Its action was reversed by pre-treatment with flumazenil and potentiated by the NMDA antagonist, MK-801. TNF-α and glutamate levels were reduced and GABA release was increased in the tests carried out. Conclusions: ISO shows low toxicity in neuronal cells and its association with PTX generated synergism in its cytotoxic action. The antinociceptive effect of ISO is due to activation of GABA and antagonism of NMDA receptors and involves the stabilization of neuronal plasma membranes leading to an imbalance in the release of neurotransmitters, favoring GABA-mediated inhibition over glutamatergic excitation. Full article