Search Results (117)

Hydrolyzed collagen (HC) derived from salmon skin is a promising source of bioactive peptides. In this study, the vasorelaxant effects and potential mechanisms of action of HC on isolated rat thoracic aorta rings were investigated using the organ bath technique. The vasorelaxant properties of HC were evaluated using aortic rings from Wistar rats pre-contracted with phenylephrine (PE) or potassium chloride (KCl). HC induced significant vasorelaxation in both endothelium-intact and endothelium-denuded rings, indicating that its mechanism of action was independent of the endothelium and involved direct effects on vascular smooth muscle cells. The vasorelaxant effect of HC was reduced when pre-contraction was induced by tetraethylammonium chloride (TEA). However, the vasodilatory effects of HC were not significantly inhibited by all K⁺ channel blockers, including glibenclamide, barium chloride (BaCl₂), or 4-aminopyridine (4-AP). Additionally, pre-incubation with prazosin, an α-adrenoceptor blocker, significantly reduced the vasorelaxation induced by HC, whereas propranolol, a β-adrenoceptor blocker, had no effect. In addition, HC inhibited CaCl₂-induced contractions induced by both PE and caffeine in a Ca²⁺-free solution. Therefore, HC exhibited the vasorelaxant effects through an endothelium-independent mechanism. The vasodilatory effects of HC were associated with the activation of K_Ca channels, suppression of PE-induced contraction via α₁-adrenergic receptor pathways, and inhibition of CaCl₂-induced contractions by modulating intracellular Ca²⁺ release and extracellular Ca²⁺ influx in vascular cells. Full article

Background/Objectives: Molecular hydrogen (H₂), a natural antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite without affecting signaling molecules such as H₂O₂ and NO. In addition, H₂ can inhibit the synthesis of inflammatory cytokines. Human and animal studies have shown that the inhalation of H₂ has a hypotensive effect. In this context, the aim of the present work was to study the effect of H₂ on the baroreflex regulation of blood pressure in rats with experimental monocrotaline-induced pulmonary hypertension (MCT) in vivo and the effects of H₂ on the reactivity of isolated rat aorta with MCT pulmonary hypertension to α₁-adrenoceptor agonists in vitro. Methods: Experiments were performed on male Wistar rats with MCT pulmonary hypertension; animals were placed in plastic chambers aerated with atmospheric air at a rate of 4 L/min with O₂ and CO₂ control. Cages with the rats of the MCT-H₂ and Control-H₂ groups were ventilated with air containing 4% H₂ twice daily for 2 h each. The MCT-Air and Control-Air groups breathed only atmospheric air. The duration of the experiment was 21 days. On day 20, blood pressure and heart rate (HR) were measured in awake animals and the baroreflex response to phenylephrine (PE) and nitroprusside (NP) was tested. In in vitro experiments, we studied the effect of adding H₂ to the perfusion solution on the responsiveness of isolated aortic preparations from MCT and control rats to the α₁-adrenoceptor agonist PE and the vasodilators NP and Acetylcholine. Results: When the effect of H₂ on the baroreflex response to NP (4.5 μg/kg) was examined in awake rats, the increase in HR was 73.1 ± 16.7 beats/min in the MCT-Air group and 48.1 ± 10.2 beats/min in the MCT-H₂ group (p < 0.01). In the Control-H₂ and Control-Air groups, there was a trend towards a lower HR in the Control-H₂ group, but the differences were not significant. No differences in HR response to PE administration were found between any of the experimental groups. Experiments on isolated aortic preparations from MCT rats showed that the addition of H₂ to the perfusion medium resulted in a 30% reduction in the maximal response to PE compared with the MCT group without hydrogen (p < 0.01), and the potency of PE (EC₅₀) decreased threefold (p < 0.05). There was a decrease in tryptase secretion, indicating an anti-inflammatory effect of H₂. Conclusions. The results demonstrate that H₂ inhalation was associated with an attenuated heart rate response to nitroprusside-induced hypotension and reduced vascular reactivity to phenylephrine in rats with pulmonary hypertension. Full article

The overdose mortality landscape has shifted from predominantly opioid exposures to a polysubstance epidemic increasingly driven by illicit fentanyl and fentanyl analogs combined with other centrally active agents. Among the co-intoxicants, veterinary α₂-adrenoceptor (α₂AR) agonists such as xylazine have emerged as clinically confounding adulterants. Recent reports from forensic toxicology, medical examiners, and border/interdiction agencies indicate that medetomidine, a veterinary sedative racemate with the highly selective α₂AR agonist enantiomer dexmedetomidine, is increasingly being detected together with fentanyl and its analogs in seized materials and postmortem assays. Prior reviews have covered these aspects. The current review synthesizes current evidence and clinical experience relevant to fentanyl + medetomidine co-exposure-induced respiratory depression—a primary cause of death. We focus on convergent µ-opioid receptor (MOR) and α₂AR signaling within key physiological substrates, including respiratory rhythm-generating networks, ascending arousal pathways, chemosensory reflex control of ventilation, and autonomic cardiovascular regulation, integrating mechanistic pharmacology, respiratory and cardiovascular toxicology, emergency-room treatment, and emerging public-health implications. Available evidence supports a model in which combined MOR and α₂AR activation produces additive-to-synergistic suppression of ventilation and consciousness, attenuation of hypoxic ventilatory drive and CO₂ responsiveness, with marked sympatholysis manifested as bradycardia and hypotension, all of which can persist beyond presumptive opioid reversal with a MOR antagonist. We discuss the implications for prehospital and emergency care. In sum, the increasing detection of medetomidine in the illicit fentanyl supply represents an emerging and potentially high-risk co-exposure pattern that may be only partially naloxone-responsive. Lastly, we highlight potential future pharmacologic countermeasures for polysubstance overdose, such as the BK-channel antagonist ENA-001, which may address naloxone-insensitive ventilatory suppression in opioid-dominant polysubstance overdose. Full article

Background/Objectives: Silodosin (SLD) is a selective α1A-adrenoceptor antagonist used in the treatment of benign prostatic hyperplasia. Bioequivalence failures have been reported for hard capsule formulations, largely due to the effect of disintegrant excipients, making soft capsules a promising alternative dosage form. This study investigated the stability of SLD soft capsules stored in two different packaging materials, PVC/PVDC and AquaBa^®. Methods: Storage temperatures at 25 °C/60%, 30 °C/65% RH, 30 °C/75% RH, and 40 °C/75% RH, and sampling were performed according to the International Council for Harmonisation (ICH) stability conditions. Assays were performed by HPLC and UV, and mass detection. Results: Degradation analysis revealed that temperature played a critical role in SLD degradation and the formation of its primary degradation products, dehydrosilodosin and impurity 1. Conclusions: AquaBa^® demonstrated superior protective properties compared to PVC/PVDC, preserving SLD content above 95% for over 12 months under 25 °C and 30 °C conditions while limiting the formation of degradation products. Nevertheless, impurity 1 exceeded its ICH Q3B (R2) specification limit (0.3%) after six months under all conditions tested, suggesting a critical interaction between SLD and excipients such as Capryol^® 90. Kinetic modeling confirmed first-order degradation kinetics for both dehydrosilodosin and impurity 1, with a faster degradation rate observed in PVC/PVDC blisters. These findings highlight the critical role of packaging in pharmaceutical stability. While AquaBa^® emerges as the preferred option for SLD soft capsules, formulation optimization remains necessary to limit impurity formation, extend shelf life, and ensure regulatory compliance. Full article

We investigated whether the functional involvement of α1-adrenergic receptors (α1-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the α1-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three α1-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of α1-AR did not affect the density of other types of adrenergic receptors, α2- and β-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective knockout of the gene encoding a single α1-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus (HY). Next, we assessed how a specific mutation affects the chronic effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of genes encoding for α1-AR subtypes, gene expression profiling, and phosphorylation of selected signaling proteins (ERK1/2, Akt, GSK3β). The main finding is that the deletion of the α1D subtype predominantly reduced the chronic effects of milnacipran at the examined transcriptomic and proteomic levels. The pattern of changes differed by gender. Our study revealed the functional diversity between α1-AR subtypes in the molecular mechanisms of antidepressants’ drug action. Full article

In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H₂S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H₂S) pathway. Individually, both H₂S and NO have also been reported to significantly improve RCBP, restore renal excretory performance, and enhance α-adrenergic receptor responsiveness in rats. The induction of LVH was performed over a period of two weeks using drinking water with caffeine and isoprenaline. Five weeks later, the rats were fed with L-arginine (1.25 g/L) as a nitrogen oxide donor. Vascular reactions to methoxamine, phenylephrine, and noradrenaline were assessed in presences and absence of 5-methylurapidil (5-MeU), BMY7378, and chloroethylclonidine (CeC) and α1-adrenoceptor antagonists. In both the Control WKY and LVH-WKY groups, combined H₂S+NO therapy significantly (p < 0.05) upregulated the renal mRNA of CSE and eNOS when compared with untreated LVH rats. The treatment also markedly increased RCBP in LVH-H₂S+NO rats relative to LVH controls. Furthermore, H₂S+NO administration enhanced the activity of α_1A, α_1B, and α_1D adrenergic receptors in mediating renal vasoconstriction. Even under receptor blockade with high doses (HDs) of 5-MeU, CeC, and BMY 7378, renal vasoconstriction responses to adrenergic agonists like NA, PE, and ME in the LVH-H₂S+NO group remained comparable to those observed in the counterpart Control-H₂S+NO group. The findings of current study suggest that simultaneous exogenous administration of H₂S and NO donors improve renal cortical blood flow, support renal function, and augment α_1A, α_1B, and α_1D adrenergic receptor responsiveness to adrenergic agonists like NA, PE, and ME in LVH rats. This effect appears to rely primarily on the eNOS/NO pathway, with partial contribution from the CSE/H₂S pathway. Full article

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Because of its high potential for spreading and its limited response to treatment, UM remains a clinical challenge. Previous studies suggest that clinical adrenergic receptor (AR) antagonists might be effective in the treatment of UM. This study reports the antitumor activity of α-blocker in UM spheroids generated from α_1A- and α_2A-AR-positive UM cell lines. These cell lines were derived from primary tumors or hepatic metastases and differed in their genetic risk status for metastasis. Drug screening with UM spheroids revealed that prazosin and doxazosin dose-dependently reduced viability, whereas terazosin, alfuzosin, silodosin, tamsulosin, and phenoxybenzamine were found to be inefficient. Prazosin induced apoptosis, resulting in the disintegration of UM spheroid morphology and growth inhibition. Additionally, prazosin prevented UM spheroid cell outgrowth and long-term survival, indicating potential for tumor control. Like the selective α_1A-AR antagonist RS17053, prazosin inhibited the formation and growth of UM spheroids stimulated by the α_1-agonist phenylephrine. This suggests a tumor-preventive effect through the blockade of α_1A-AR. The present study highlights the responses of UM spheroids to α-AR antagonists and demonstrates that prazosin, doxazosin, or RS17053 may be a treatment option for preventing UM tumor recurrence or metastasis. Full article

Wound healing is impaired under diabetic conditions due to reduced angiogenesis, thereby increasing the risk of wound-healing complications. Studies have shown that inhibition of α- and β-adrenoceptors delays wound healing. This study investigates the effects of topical salbutamol (TS) on STZ-induced diabetic wound healing in rats. The rats were divided into two initial groups: non-diabetic and diabetic. Diabetes mellitus was induced in the second group with STZ (65 mg/kg). Excision wounds were inflicted on the dorsal thoracic region, 1–1.5 cm away from the vertebral column on either side, following anesthesia on all groups. Group 2 was subdivided into untreated diabetic wounds, low-dose-TS-treated diabetic wounds (6.25 mg/mL), medium-dose-TS-treated diabetic wounds (12.5 mg/mL), and high-dose-TS-treated diabetic wounds (25 mg/mL), and were monitored for 14 days. Percentage wound contraction and the time required for complete wound closure were observed and recorded. In addition, oxidative stress and inflammatory markers such as NO, CRP, MPO, TGF-β1, TNF-α, IL-6, IL-1β, NO, and hexosamine were estimated in wound exudates and tissue over 14 days. TS treatment resulted in 100% wound contraction in all treated wounds within 14 days compared to untreated non-diabetic and diabetic wounds. Increased NO, TGF-β1, and hexosamine activity was observed in TS-treated wounds when compared to untreated diabetic wounds. In addition, TS treatment decreased the activity of IL-1β, TNF-α, IL-6, CRP, and MPO, all of which were elevated in the untreated diabetic wounds. The current study shows that the application of TS significantly improved diabetic wound contraction and aided the healing process. Angiogenic markers, such as TGF-β1 and NO, were prominently increased, supporting the role of sympathetic nerve stimulation in angiogenesis. Full article

Objectives: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. Methods: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. Results: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, p = 0.049) but less absolute IPSS improvement (p < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS_1–4) from the baseline to week 8 did not differ significantly (−5.78 ± 5.29 vs. −6.0 ± 4.54, p = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS_1–4 improvement (−6.25 ± 4.60 vs. 0.0 ± 9.53, p = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, p < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax_1–4 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, p = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (p = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). Conclusions: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings. Full article

Fatty acids (FAs) play a crucial role in human physiology, including energy production and serving as signaling molecules. However, a dysregulation in their balance can lead to multiple disorders, such as obesity and metabolic syndrome. These pathological conditions alter the balance between the heart’s energetic substrates, promoting an increased reliance on FAs and decreased cardiac efficiency. A therapeutic application of a non-psychotropic phytocannabinoid, cannabigerol (CBG), seems to be a promising target since it interacts with different receptors and ion channels, including cannabinoid receptors—CB₁ and CB₂, α2 adrenoceptor, or 5-hydroxytryptamine receptor. Therefore, in the current study, we evaluated a concentration-dependent effect of CBG (2.5 µM, 5 µM, and 10 µM) on H9c2 cardiomyocytes in lipid overload conditions. Gas–liquid chromatography and Western blotting techniques were used to determine the cellular lipid content and the level of selected proteins involved in FA metabolism, glucose transport, and the insulin signaling pathway. The glucose uptake assay was performed using a colorimetric method. Eighteen-hour CBG treatment in the highest concentration (10 µM) significantly diminished the accumulation of diacylglycerols (DAGs) and the saturation status of this lipid fraction. Moreover, the same concentration of CBG markedly decreased the level of FA transporters, namely fatty acid translocase (CD36) and plasma membrane fatty acid-binding protein (FABPpm), in the presence of palmitate (PA) in the culture medium. The results of our experiment suggest that CBG can significantly modulate lipid storage and composition in cardiomyocytes, thereby protecting against lipid-induced cellular dysfunction. Full article

Background/Objectives: Norepinephrine (NE) plays a crucial role in modulating cognitive processes via α2A-adrenoceptors (α2A-ARs) within the prefrontal cortex (PFC), an essential brain region responsible for higher cognitive functions. The α2A-ARs are found on both postsynaptic and presynaptic membranes in the PFC. Previous studies have shown that presynaptic α2A-ARs, predominantly located at NE terminals, function as autoreceptors that inhibit NE release. However, the expression of α2A-ARs at non-NE terminals, such as glutamate and GABA, remains ambiguous. To clarify the expression patterns and potential roles of α2A-ARs at non-NE terminals, we investigated their presence at the axon terminals of excitatory glutamate neurons and inhibitory GABA neurons in the rat PFC using immunofluorescence double-labeling, whole-cell patch-clamp recordings, and pharmacological approaches. Methods: To clarify the expression patterns and potential roles of α2A-ARs at non-NE terminals, we investigated their presence at the axon terminals of glutamate neurons and GABA neurons in the rat PFC using immunofluorescence double-labeling, whole-cell patch-clamp recordings, and pharmacological approaches. Results: Our findings delineated the distribution of α2A-ARs at the axon terminals of both glutamate and GABA neurons, and the expression of α2A-AR in the pyramidal neurons within the rat PFC as well. Furthermore, we employed the selective α2A-AR agonist guanfacine to assess the functional role of presynaptic α2A-ARs at these non-NE terminals. Following the application of the PKA inhibitor PKI_5–24 to block postsynaptic α2A-AR function, guanfacine still significantly decreased the frequency (not the amplitude) of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in layer 5–6 pyramidal neurons. Notably, the frequency reduction induced by guanfacine persisted even after the depletion of presynaptic NE vesicles. Conclusions: These findings offer a comprehensive analysis of presynaptic α2A-AR expression and function in the PFC, revealing for the first time their role as heteroreceptors that modulate the release of glutamate and GABA. Our results provide morphological and electrophysiological insights into a potential mechanism through which α2A-AR stimulation enhances cognitive functions. Full article

β-adrenoceptors (BARs) are involved in vascular endothelial growth factor (VEGF) production during retinal neovascularization. Here, using human retinal endothelial and Müller cells (hRECs and MIO-M1, respectively), we evaluated the effects exerted by hypoxia on BARs, hypoxia-inducible factor-1α subunit (HIF-1α) and VEGF, as well as the involvement of BAR3 and nitric oxide synthase (NOS) enzymes in hypoxia-induced VEGF production. We altered oxygen availability through a hypoxic incubator. BARs, HIF-1 α and VEGF levels were evaluated. Cells were treated with the BAR3 antagonist SR59230A, different NOS inhibitors or the NO donor SNAP. The influence of the BAR3/NOS axis on hypoxic VEGF production was assessed. Hypoxia upregulated BAR3, HIF-1α and VEGF in hRECs and MIO-M1 cells. SR59230A counteracted hypoxia-dependent VEGF increase in both cell lines, exerting no effect on HIF-1α upregulation. Treatments with NOS inhibitors prevented the hypoxia-dependent VEGF increase, while SNAP abrogated the effect of SR59230A in reducing hypoxia-induced VEGF upregulation. The present results corroborate the hypothesis that in the hypoxic retina, BAR3 influence on VEGF production is mediated by NO and suggest that, at least in endothelial and Müller cells, BAR3 activity is necessary to allow the HIF-1-mediated VEGF upregulation. Full article

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus and a leading cause of blindness in the working-age population. Current pharmacological treatments counteract DR’s later stages without targeting the earlier disease phases. Using computational approaches, our group previously identified the α1D and α2C adrenoceptors (α1DR and α2CR) as new putative drug targets for DR. Therefore, the aim of this work was to validate the role of these receptors in an in vitro model of DR, i.e., retinal pigmented epithelial cells (ARPE-19) challenged with high glucose (HG, 50 mM). We examined the effects of selective α1DR and α2CR agonists and antagonists on hyperglycemia-induced mitochondrial dysfunction and blood retinal barrier breakdown. Seahorse XFe was employed to assess the oxygen consumption rate and extracellular acidification rate. The integrity of the ARPE-19 barrier was evaluated through transepithelial electrical resistance measurements and a sodium fluorescein permeability test. α1DR pharmacological modulation through the α1DR antagonist BMY 7378 (0.1–1 µM, 24 h), but not α2CR, significantly attenuated HG-induced mitochondrial dysfunction. BMY 7378 (0.1–1 µM, 48 h) also prevented HG-mediated damage to retinal epithelial integrity. In contrast, the α1DR agonist phenylephrine (1–10 μM, 24 h) further reduced ARPE-19 mitochondrial activity compared to HG, indicating that α1D activation is directly implicated in DR-mediated mitochondrial dysfunction. In conclusion, the current in vitro study validated α1DR as a pharmacological target for DR. Full article

Formosan serows are an endemic species in Taiwan. Alfaxalone, a γ-aminobutyric acid_A agonist, induces or maintains anesthesia in various veterinary species with reported potential adverse effects of respiratory depression and tachycardia. α2-Adrenoceptor agonists exert sedative and muscle relaxation effects, along with substantial cardiovascular adverse effects. Here, we aimed to evaluate the anesthetic effects of alfaxalone combined with xylazine or dexmedetomidine (AX vs. AD, respectively) in Formosan serows. In this randomized, masked study, AX was administered to four serows, and AD was administered to five serows intramuscularly via blow dart. The time and score of induction and recovery were recorded. Post-intubation, isoflurane was administered for maintenance anesthesia. Heart rate (HR), respiratory rate (RR), peripheral saturation of oxygenation (SpO₂), rectal temperature (RT), and end-tidal CO₂ (EtCO₂) were recorded every five to eight minutes. Atipamezole and tolazoline were administered to antagonize dexmedetomidine and xylazine post-procedure, respectively. Both combinations allowed smooth induction and recovery. The AD group exhibited significantly lower HR and SpO₂ and significantly higher RT and EtCO₂ than the AX group (both p < 0.01). The AD-treated serows exhibited notable muscle rigidity after induction and significant hypoventilation and hypoxemia during the procedure. Although alfaxalone combined with dexmedetomidine or xylazine can produce satisfactory induction and recovery in Formosa serows, notable hypoxemia and hypoventilation are induced by the alfaxalone–dexmedetomidine combination compared to the alfaxalone–xylazine combination. Full article

Nociceptive information is transmitted by action potentials (APs) through primary afferent neurons from the periphery to the central nervous system. Voltage-gated Na⁺ channels are involved in this AP production, while transient receptor potential (TRP) channels, which are non-selective cation channels, are involved in receiving and transmitting nociceptive stimuli in the peripheral and central terminals of the primary afferent neurons. Peripheral terminal TRP vanilloid-1 (TRPV1), ankylin-1 (TRPA1) and melastatin-8 (TRPM8) activation produces APs, while central terminal TRP activation enhances the spontaneous release of L-glutamate from the terminal to spinal cord and brain stem lamina II neurons that play a pivotal role in modulating nociceptive transmission. There is much evidence demonstrating that chemical compounds involved in Na⁺ channel (or nerve AP conduction) inhibition modify TRP channel functions. Among these compounds are local anesthetics, anti-epileptics, α₂-adrenoceptor agonists, antidepressants (all of which are used as analgesic adjuvants), general anesthetics, opioids, non-steroidal anti-inflammatory drugs and plant-derived compounds, many of which are involved in antinociception. This review mentions the modulation of Na⁺ channels and TRP channels including TRPV1, TRPA1 and TRPM8, both of which modulations are produced by pain-related compounds. Full article