Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial.

INTRODUCTION: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. METHODS: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. RESULTS: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. CONCLUSIONS: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve ß-Cell Mass and Function in Type 2 Diabetes?

Improvement of insulin secretion by pancreatic ß-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the Helodermatidae family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic ß-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and ß-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting ß-cells, which would tackle the progression of the disease.

Toxic Animal-Based Medicinal Materials Can Be Effective in Treating Endometriosis: A Scoping Review.

Animal toxins and venoms have recently been developed as cancer treatments possessing tumor cell growth-inhibitory, antiangiogenesis, and proapoptotic effects. Endometriosis is a common benign gynecological disorder in reproductive-age women, and no definite treatment for this disorder is without severe side effects. As endometriosis and malignant tumors share similar characteristics (progressive, invasive, estrogen-dependent growth, and recurrence), animal toxins and venoms are thought to be effective against endometriosis. The objective of this study was to outline studies using toxic animal-based medicinal materials (TMM) as endometriosis treatment and to explore its clinical applicability. Preclinical and clinical studies using TMM were searched for in four databases from inception to October 2020. A total of 20 studies of TMM on endometriosis were included. In eight clinical studies, herbal medicines containing TMM were effective in relieving symptoms of endometriosis, with no side effects. In twelve experimental studies, the main therapeutic mechanisms of TMM against endometriosis were proapoptotic, antiangiogenesis, estrogen level-reducing, and possible anti-inflammatory effects. TMM are thus considered promising sources for the development of an effective treatment method for endometriosis. Further studies are needed to clarify the therapeutic mechanism of TMM against endometriosis and to provide sufficient grounds for clinical application.

Antimicrobials from Venomous Animals: An Overview.

The inappropriate or excessive use of antimicrobial agents caused an emerging public health problem due to the resulting resistance developed by microbes. Therefore, there is an urgent need to develop effective antimicrobial strategies relying on natural agents with different mechanisms of action. Nature has been known to offer many bioactive compounds, in the form of animal venoms, algae, and plant extracts that were used for decades in traditional medicine. Animal venoms and secretions have been deeply studied for their wealth in pharmaceutically promising molecules. As such, they were reported to exhibit many biological activities of interest, such as antibacterial, antiviral, anticancer, and anti-inflammatory activities. In this review, we summarize recent findings on the antimicrobial activities of crude animal venoms/secretions, and describe the peptides that are responsible of these activities.

Animal venoms: therapeutic tools for tackling Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative pathology of the central nervous system, mainly involving the selective and progressive loss of dopaminergic neurons from the substantia nigra, resulting in motor and non-motor symptoms. PD remains an incurable ailment; thus, treatments are limited to symptom alleviation. With long-term use, conventional treatments can become inefficient, often triggering possible side effects. Considering these drawbacks, drug discovery constantly turns to nature as a source of efficient therapeutics. Thus, this review explores animal venoms as a rich source of bioactive compounds with potent neuropharmacological profiles for the development of effective adjuvant treatments with fewer side effects, ultimately aiming for the neuroprotection of dopaminergic neurons and the symptomatic relief of PD.

Venom as therapeutic weapon to combat dreadful diseases of 21st century: A systematic review on cancer, TB, and HIV/AIDS.

Cancer and infectious diseases are the preeminent causes of human morbidities and mortalities worldwide. At present, chemotherapy, radiotherapy, immunotherapy, and gene therapy are considered as predominant options in order to treat cancer. But these therapies provide inadequate consequences by affecting both the normal and tumor cells. On the other hand, tuberculosis (TB), and HIV (human immunodeficiency virus) infections are significant threats, causing over a million mortalities each year. The extensive applications of antibiotics have caused the microbes to acquire resistance to the existing antibiotics. With the emerging dilemma of drug resistant microbes, it has become imperative to identify novel therapeutic agents from natural sources as emphatic alternative approach. Over the past few decades, venoms derived from several reptiles, amphibians, and arthropods including snakes, scorpions, frogs, spiders, honey bees, wasps, beetles, caterpillars, ants, centipedes, and sponges have been identified as efficient therapeutics. Venoms constitute plethora of bioactive components, particularly peptides, enzymes, and other chemical entities, which exhibit a large array of anticancer and anti-pathogenic activities. This review highlights the panorama of bioactive components of animal venoms divulging the anticancer, anti-tubercular, and anti-HIV activities. In a nutshell, this context discloses the decisive role of animal venoms as alternative natural resources to combat these deadly diseases of 21st century, and propounding the plausible development of new therapeutic drugs in the present era.

Potential Uses of Isolated Toxin Peptides in Neuropathic Pain Relief: A Literature Review.

Neuropathic pain is a subset of chronic pain that is caused by neurons that are damaged or firing aberrantly in the peripheral or central nervous systems. The treatment guidelines for neuropathic pain include antidepressants, calcium channel α2 delta ligands, topical therapy, and opioids as a second-line option. Pharmacotherapy has not been effective in the treatment of neuropathic pain except in the treatment of trigeminal neuralgia with carbamazepine. The inability to properly treat neuropathic pain causes frustration in both the patients and their treating physicians. Venoms, which are classically believed to be causes of pain and death, have peptide components that have been implicated in pain relief. Although some venoms are efficacious and have shown benefits in patients, their side-effect profile precludes their more widespread use. This review identifies and explores the use of venoms in neuropathic pain relief. This treatment can open doors to potential therapeutic targets. We believe that further research into the mechanisms of action of these receptors as well as their functions in nature will provide alternative therapies as well as a window into how they affect neuropathic pain.

A novel selective VPAC2 agonist peptide-conjugated chitosan modified selenium nanoparticles with enhanced anti-type 2 diabetes synergy effects.

A novel neuroendocrine peptide, pituitary adenylate cyclase activating peptide (PACAP), was found to have an important role in carbohydrate or lipid metabolism and was susceptible to dipeptidyl peptidase IV degradation. It can not only mediate glucose-dependent insulin secretion and lower blood glucose by activating VPAC2 receptor, but also raise blood glucose by promoting glucagon production by VPAC1 receptor activation. Therefore, its therapeutic application is restricted by the exceedingly short-acting half-life and the stimulatory function for glycogenolysis. Herein, we generated novel peptide-conjugated selenium nanoparticles (SeNPs; named as SCD), comprising a 32-amino acid PACAP-derived peptide DBAYL that selectively binds to VPAC2, and chitosan-modified SeNPs (SeNPs-CTS, SC) as slow-release carrier. The circulating half-life of SCD is 14.12 h in mice, which is 168.4-and 7.1-fold longer than wild PACAP (~5 min) and DBAYL (~1.98 h), respectively. SCD (10 nmol/L) significantly promotes INS-1 cell proliferation, glucose uptake, insulin secretion, insulin receptor expression and also obviously reduces intracellular reactive oxygen species levels in H2O2-injured INS-1 cells. Furthermore, the biological effects of SCD are stronger than Exendin-4 (a clinically approved drug through its insulinotropic effect), DBAYL, SeNPs or SC. A single injection of SCD (20 nmol/kg) into db/db mice with type 2 diabetes leads to enhanced insulin secretion and sustained hypoglycemic effect, and the effectiveness and duration of SCD in enhancing insulin secretion and reducing blood glucose levels are much stronger than Exendin-4, SeNPs or SC. In db/db mice, chronic administration of SCD by daily injection for 12 weeks markedly improved glucose and lipid profiles, insulin sensitivity and the structures of pancreatic and adipose tissue. The results indicate that SC can play a role as a carrier for the slow release of bioactive peptides and SCD could be a hopeful therapeutic against type 2 diabetes through the synergy effects of DBAYL and SeNPs.

Comparison of exenatide and acarbose on intra-abdominal fat content in patients with obesity and type-2 diabetes: A randomized controlled trial.

OBJECTIVE: To investigate exenatide, a GLP-1 analogue, compared with acarbose, for intra-abdominal fat reduction in patients with obesity and type-2 diabetes. METHODS: This randomized controlled trial included 36 patients with obesity and type-2 diabetes, who were metformin-unresponsive, receiving metformin/exenatide (GLP-1 group) or metformin/acarbose (control group) for 3 months. Primary end-point: intra-abdominal fat content from baseline to 3 months; Secondary end-points: changes in fasting blood glucose, glycated haemoglobin (HbAlc), fasting insulin, blood lipids, weight, body mass index, and inflammatory cytokines from baseline to 3 months. RESULTS: Intra-abdominal fat content decreased in the GLP-1 group from baseline to 3 months (17,947±5804; 13,717±3628mm2, P=0.001, respectively), but was not significantly reduced in the control group (P=0.197) and at 3 months post-treatment, it was significantly lower in the GLP-1 group than control group (P=0.043). Glucose control, measured by HbA1c (GLP-1: 9.72±1.38; 7.09±0.60%, P<0.001, 9.46±1.25; 7.42±0.84%, P<0.001, respectively) and insulin resistance index LN(HOMA-IR) (GLP-1: 1.58±0.40; 1.01±0.33, P<0.001, Control: 1.53±0.57; 1.10±0.33, P=0.003, respectively) significantly improved in both groups with no significant difference between them. TNF-α, IL-6, and leptin were lower and adiponectin levels higher in the GLP-1 group at 3 months compared with baseline (all P<0.05), but not significantly changed in the control group. TNF-α, IL-6 and leptin levels were similar between groups. Adiponectin level was higher in the GLP-1 group than the control group at 3 months (P=0.025). CONCLUSION: Combined exenatide/metformin reduced intra-abdominal fat content, and enhanced insulin resistance and inflammatory status in patients with obesity and type-2 diabetes, representing a novel treatment regimen.

Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing.

BACKGROUND: Diabetes disregulates inflammatory responses and impairs vascular function in wounds. Glucagon-like peptide-1 receptor (Glp-1R) agonists are hypoglycemic agents with pleiotropic vascular protective and anti-inflammatory effects. The therapeutic potential of a Glp-1 analogue in a diabetic rat model of excisional wound injury was investigated. MATERIALS AND METHODS: Excisional wounds were created on the dorsum of streptozotocin-induced diabetic rats, which received placebo or Glp-1 analogue exendin-4 (Ex4; 0.5 µg/kg/d, i.p.) for 2 wk. The final-to-initial wound area ratio was measured for 14 d. Levels of superoxide anions and proinflammatory cytokines in the wound were determined. Angiogenesis was assessed using the Matrigel assay. Expression levels of proangiogenic factors and extracellular matrix proteins were measured. RESULTS: Ex4 restored wound closure in diabetic rats and significantly suppressed the generation of superoxide anions and interleukin-6 in wounds. The number of circulating endothelial progenitor (CD34+/KDR+) cells increased significantly in Ex4-treated diabetic rats, which also showed increased capillary tube formation. Protein levels of vascular endothelial growth factor receptor-2, phosphorylated endothelial nitric oxide synthase, matrix metalloproteinase-2, and transforming growth factor-ß were increased in diabetic rats receiving Ex4 therapy. Ex4-enhanced vascularity, dermal regeneration, and epidermal regeneration, while it decreased hemorrhaging and increased the number of proliferative cells in the dermis. CONCLUSIONS: Ex4 accelerated excisional wound healing in subjects with diabetes. Glp-1R activation attenuates inflammatory response and enhances angiogenesis during the early proliferation phase of wound healing in diabetic subjects, while it enhances transforming growth factor-ß/matrix metalloproteinase-mediated regeneration during the maturation phase. These results suggest that Ex4 could be used as a standard hypoglycemic agent in diabetic patients with wound injury.

Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies.

Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential 'antioxidant' activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications.

[Glucagon-like peptide-1 (GLP-1) mimetics: a new treatment for Alzheimer's disease?]. / Análogos del glucagon-like peptide-1 (GLP-1): ¿una nueva estrategia de tratamiento para la enfermedad de Alzheimer?

INTRODUCTION: The glucagon-like peptide-1 (GLP-1) mimetics are an established therapeutic option for patients with type 2 diabetes. However, the properties of the GLP-1 mimetics go beyond the strict metabolic control of the patients with diabetes. The neuroprotective effects of GLP-1 have been shown in recent studies opening new areas of research in neurodegenerative diseases such as Alzheimer's disease (AD), among others. AIM. Systematic review including experimental studies and human clinical trials demonstrating the neuroprotective properties of GLP-1 mimetics in AD. DEVELOPMENT: The experimental studies that have been conducted in rodent models of AD have demonstrated the neuroprotective properties of GLP-1 in the central nervous system reducing beta-amyloid plaques, the oxidative stress and the inflammatory brain response. Clinical trials in patients with cognitive impairment and AD testing the effects of GLP-1 analogs have recently started. CONCLUSION: The GLP-1 analogs have neuroprotective properties. Considering that type 2 diabetes is a risk factor for cognitive impairment and dementia, the benefits of GLP-1 mimetics on cognition must be considered. Likewise, the GLP-1 mimetics represent a promising treatment for neurodegenerative diseases such as AD.

TITLE: Analogos del glucagon-like peptide-1 (GLP-1): una nueva estrategia de tratamiento para la enfermedad de Alzheimer?Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.

GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

[Effect of byetta on renal osmoregulatory function in patients with diabetes mellitus].

The renal osmoregulatory function was studied in patients with type 2 diabetes mellitus (DM). The renal response to water loading (0.7% b.w.) and simultaneous exenatide (byetta) injection (5 microg) exhibited variation and was dependent on the degree of hyperglycemia. Effective solute-free water excretion was observed in patients with well-controlled DM (HbAlc 6.0 +/- 0.1%), in which CH20 changed from -0.67 +/- 0.2 mL/min to 0.72 +/- 0.2 mL/min. This reaction was absent in patients with poorly controlled DM (HbAlc 8.8 +/- 0.6%) and the process of solute-free water reabsorption prevailed: -CH20 = -1.06 +/- 0.1 mL/min in control period vs. -0.99 +/- 0.1 mL/min after treatment. Thus, byetta increases the efficiency of osmoregulation and accelerates the excretion of excess water in patients with compensated carbohydrate metabolism.

Glucagon-like peptide-1 receptor agonists for weight loss in adult patients without diabetes.

PURPOSE: The efficacy and safety of glucagon-like peptide (GLP)-1 receptor agonists for weight loss in adult patients without diabetes is reviewed. SUMMARY: GLP-1 receptor agonists have been associated with significant weight loss in patients with diabetes, raising the question of whether these agents could be used for weight loss in patients without diabetes. The mechanism by which GLP-1 receptor agonists induce weight loss is believed to be related to multiple actions involving the brain and gastrointestinal tract, with the primary action related to an increase in satiety. Trials examining the effects of GLP-1 receptor agonists for weight loss have compared exenatide, liraglutide, and orlistat. Of the studies completed to date, the majority of patients have been enrolled in trials involving liraglutide. Based on the reviewed literature, both exenatide 10 µg twice daily and liraglutide in dosages of up to 3 mg daily resulted in significant weight loss in patients without diabetes. A decrease in the proportion of patients with prediabetes was also found in studies of liraglutide. Nausea and vomiting were the most frequently reported adverse events in patients from these studies. Symptomatic hypoglycemia was reported in only one study with liraglutide in patients without diabetes and was not objectively confirmed by laboratory data. A higher frequency of psychiatric disorders, specifically insomnia, was reported by patients taking high doses of liraglutide. CONCLUSION: GLP-1 receptor agonists offer a reasonable alternative for nondiabetic patients not able to achieve weight-loss goals with lifestyle modifications alone.

The medicinal use of venoms and toxins.

Venoms have long since been known to have therapeutic value. Venoms have been characterised into their individual components and each of their functions extensively studied. These components of venoms and toxins show potential as antihypertensive, anticoagulant, fibrinolytic, anticancerous, immunomodulators, muscle relaxant, etc. Only the most promising and FDA approved and therapeutic options have been discussed here eg, hannalgesin, epibatidine, ancrod, lepirudin, fibrolase, lebecetin, pseutarin, captopril, eristostatin, botox.

Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression.

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 µg of vehicle or 1.5 µg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.

The fetal origins of the metabolic syndrome: can we intervene?

Epidemiological studies have suggested that metabolic programming begins during fetal life and adverse events in utero are a critical factor in the etiology of chronic diseases and overall health. While the underlying molecular mechanisms linking impaired fetal development to these adult diseases are being elucidated, little is known about how we can intervene early in life to diminish the incidence and severity of these long-term diseases. This paper highlights the latest clinical and pharmaceutical studies addressing how dietary intervention in fetal and neonatal life may be able to prevent aspects of the metabolic syndrome associated with IUGR pregnancies.

Venom's antinociceptive property in the primitive ant Dinoponera quadriceps.

ETHNOPHARMACOLOGICAL RELEVANCE: In northeastern Brazil, Dinoponera (Ponerinae) ants macerate are used to treat ear ache and its sting, rheumatism, and back pain. Such a popular use is a relevant fact that called for experimental evaluation of the antinociceptive activity of Dinoponera venom. MATERIALS AND METHODS: Dinoponera quadriceps venom (DqV; 5-500 µg/kg; i.v.) or morphine (3.4 mg/kg; s.c.) were evaluated in mice models of nociception (n=8 animals/group). Negative controls received sterile saline (0.9% NaCl; i.v.). RESULTS: DqV showed 64% protein content and exhibited antinociceptive activity, without affecting motor function, in the tests: formalin (72%), writhing (52%), von Frey (71%) and hot plate (45%). The antinociceptive activity was abolished under protein denaturant conditions. CONCLUSIONS: This study provided the first demonstration of the antinociceptive property of Dinoponera quadriceps venom in mice models of chemical, mechanical and thermal nociception, corroborating the popular use and suggesting its potential therapeutic utilization in painful conditions.