RESUMO
Neuropathic pain (NP) is a challenging condition to treat, as the need for new drugs to treat NP is an unmet goal. We investigated the analgesic potential of a new sulfated disaccharide compound, named BIS014. Oral administration (p.o.) of this compound induced ameliorative effects in formalin-induced nociception and capsaicin-induced secondary mechanical hypersensitivity in mice, but also after partial sciatic nerve transection (spared nerve injury), chemotherapy (paclitaxel)-induced NP, and diabetic neuropathy induced by streptozotocin. Importantly, BIS014, at doses active on neuropathic hypersensitivity (60 mg/kg/p.o.), did not alter exploratory activity or motor coordination (in the rotarod test), unlike a standard dose of gabapentin (40 mg/kg/p.o.) which although inducing antiallodynic effects on the NP models, it also markedly decreased exploration and motor coordination. In docking and molecular dynamic simulation studies, BIS014 interacted with TRPV1, a receptor involved in pain transmission where it behaved as a partial agonist. Additionally, similar to capsaicin, BIS014 increased cytosolic Ca2+ concentration ([Ca2+]c) in neuroblastoma cells expressing TRPV1 receptors; these elevations were blocked by ruthenium red. BIS014 did not block capsaicin-elicited [Ca2+]c transients, but inhibited the increase in the firing rate of action potentials in bradykinin-sensitized dorsal root ganglion neurons stimulated with capsaicin. Perspective: We report that the oral administration of a new sulfated disaccharide compound, named BIS014, decreases neuropathic pain from diverse etiology in mice. Unlike the comparator gabapentin, BIS014 does not induce sedation. Thus, BIS014 has the potential to become a new efficacious non-sedative oral medication for the treatment of neuropathic pain.
Assuntos
Capsaicina , Neuralgia , Camundongos , Animais , Capsaicina/efeitos adversos , Ácido Hialurônico/farmacologia , Gabapentina , Canais de Cátion TRPV , Hiperalgesia/tratamento farmacológicoRESUMO
The latest trends in cancer research and nanomedicine focus on using nanocarriers to target cancer stem cells (CSCs). Specifically, lipid liquid nanocapsules are usually developed as nanocarriers for lipophilic drug delivery. Here, we developed olive oil liquid NCs (O2LNCs) functionalized by covalent coupling of an anti-CD44-fluorescein isothiocyanate antibody (αCD44). First, O2LNCs are formed by a core of olive oil surrounded by a shell containing phospholipids, a nonionic surfactant, and deoxycholic acid molecules. Then, O2LNCs were coated with an αCD44 antibody (αCD44-O2LNC). The optimization of an αCD44 coating procedure, a complete physicochemical characterization, as well as clear evidence of their efficacy in vitro and in vivo were demonstrated. Our results indicate the high targeted uptake of these αCD44-O2LNCs, and the increased antitumor efficacy (up to four times) of paclitaxel-loaded-αCD44-O2LNC compared to free paclitaxel in pancreatic CSCs (PCSCs). Also, αCD44-O2LNCs were able to selectively target PCSCs in an orthotopic xenotransplant in vivo model.
Assuntos
Nanocápsulas , Neoplasias Pancreáticas , Humanos , Células-Tronco Neoplásicas , Azeite de Oliva , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
In breast cancer (BC), the presence of cancer stem cells (CSCs) has been related to relapse, metastasis, and radioresistance. Radiotherapy (RT) is an extended BC treatment, but is not always effective. CSCs have several mechanisms of radioresistance in place, and some miRNAs are involved in the cellular response to ionizing radiation (IR). Here, we studied how IR affects the expression of miRNAs related to stemness in different molecular BC subtypes. Exposition of BC cells to radiation doses of 2, 4, or 6 Gy affected their phenotype, functional characteristics, pluripotency gene expression, and in vivo tumorigenic capacity. This held true for various molecular subtypes of BC cells (classified by ER, PR and HER-2 status), and for BC cells either plated in monolayer, or being in suspension as mammospheres. However, the effect of IR on the expression of eight stemness- and radioresistance-related miRNAs (miR-210, miR-10b, miR-182, miR-142, miR-221, miR-21, miR-93, miR-15b) varied, depending on cell line subpopulation and clinicopathological features of BC patients. Therefore, clinicopathological features and, potentially also, chemotherapy regimen should be both taken into consideration, for determining a potential miRNA signature by liquid biopsy in BC patients treated with RT. Personalized and precision RT dosage regimes could improve the prognosis, treatment, and survival of BC patients.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Família Aldeído Desidrogenase 1/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Medicina de Precisão , Radiação Ionizante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estatísticas não Paramétricas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptorspecific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.
Assuntos
Medição da Dor/efeitos dos fármacos , Tetrodotoxina/farmacologia , Dor Visceral/tratamento farmacológico , Analgésicos/farmacologia , Animais , Capsaicina/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Cistite/tratamento farmacológico , Cistite/metabolismo , Modelos Animais de Doenças , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfina/farmacologia , Mostardeira , Nociceptores/metabolismo , Óleos de Plantas/farmacologia , Canais de Sódio/metabolismo , Dor Visceral/metabolismoRESUMO
The sigma-1 receptor is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system. Sigma-1 receptors interact with a variety of protein targets to modify their function. These targets include several G-protein-coupled receptors such as the µ-opioid receptor, and ion channels such as the N-methyl-D-aspartate receptor (NMDAR). Sigma-1 antagonists modify the chaperoning activity of sigma-1 receptor by increasing opioid signaling and decreasing NMDAR responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions. However, the participation in pain relief of other protein partners of sigma-1 receptors in addition to opioid receptors and NMDARs cannot be ruled out. The enhanced opioid antinociception by sigma-1 antagonism is not accompanied by an increase in opioid side effects , including tolerance, dependence or constipation, so the use of sigma-1 antagonists may increase the therapeutic index of opioids. Furthermore, sigma-1 antagonists (in the absence of opioids) have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (the antineoplastic paclitaxel), and more recently in inflammatory and ischemic pain. Although most studies attributed the analgesic properties of sigma-1 antagonists to their central actions, it is now known that peripheral sigma-1 receptors also participate in their effects. Overwhelming preclinical evidence of the role of sigma-1 receptors in pain has led to the development of the first selective sigma-1 antagonist with an intended indication for pain treatment, which is currently in Phase II clinical trials.
Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Animais , Tolerância a Medicamentos/fisiologia , Humanos , Receptores Opioides mu/metabolismo , Receptor Sigma-1RESUMO
We evaluated the effects of σ1-receptor inhibition on µ-opioid-induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several µ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral µ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated µ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The µ-opioid antinociception potentiated by σ1 inhibition (by σ1-receptor knockout or σ1-pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and σ1 receptor cannot account for our results, since the former lacked affinity for σ1 receptors (labeled with [(3)H](+)-pentazocine). A peripheral role for σ1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, σ1-receptor inhibition did not alter fentanyl- or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, σ1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral µ-opioid analgesia without affecting opioid-induced constipation.
Assuntos
Analgésicos Opioides/farmacologia , Medição da Dor/métodos , Receptores Opioides mu/fisiologia , Receptores sigma/fisiologia , Analgésicos Opioides/antagonistas & inibidores , Animais , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/genética , Constipação Intestinal/metabolismo , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Camundongos , Camundongos Knockout , Receptores Opioides mu/metabolismo , Receptores sigma/deficiência , Receptores sigma/genética , Receptor Sigma-1RESUMO
We studied the modulation of morphine-induced mechanical antinociception and side effects by σ1 receptor inhibition. Both wild-type (WT) and σ1 receptor knockout (σ1-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ1-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with σ1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective σ1 agonist PRE-084. Although the local administration of morphine (50-200 µg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in σ1-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with σ1 antagonists and the opioid. None of the σ1 antagonists tested enhanced morphine-antinociception in σ1-KO mice, confirming a σ1-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ1-KO mice. These results cannot be explained by a direct interaction of σ1 ligands with µ-opioid receptors or adaptive changes of µ-receptors in σ1-KO mice, given that [(3)H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ1 drugs tested bound to µ-opioid receptors. These results show that σ1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.
Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Receptores sigma/antagonistas & inibidores , Analgésicos Opioides/uso terapêutico , Animais , Sinergismo Farmacológico , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Motilidade Gastrointestinal/efeitos dos fármacos , Membro Posterior/metabolismo , Hiperalgesia/tratamento farmacológico , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Prosencéfalo/metabolismo , Receptores sigma/genética , Receptores sigma/metabolismo , Medula Espinal/metabolismo , Trítio , Receptor Sigma-1RESUMO
UNLABELLED: Sigma-1 (σ(1)) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and σ(1) receptor knockout (σ(1)-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16-64 mg/kg, subcutaneously) and S1RA (32-128 mg/kg, subcutaneously), 2 selective σ(1) receptor antagonists that bind to the σ(1) receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ(1)-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg, intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated kinase (pERK) in WT but not in σ(1)-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel dose prevented the development of cold and mechanical allodynia in WT mice. Moreover, the acute administration of both σ(1) receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ(1) receptors play a key role in paclitaxel-induced painful neuropathy. PERSPECTIVE: Antagonists of the σ(1) receptor may have therapeutic value for the treatment and/or prevention of paclitaxel-induced neuropathic pain. This possibility is especially interesting in the context of chemotherapy-induced neuropathy, where the onset of nerve damage is predictable and preventive treatment could be administered.
Assuntos
Antineoplásicos Fitogênicos , Neuralgia/induzido quimicamente , Paclitaxel , Receptores sigma/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Encéfalo/metabolismo , Temperatura Baixa , Feminino , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Membranas/efeitos dos fármacos , Membranas/metabolismo , Camundongos , Camundongos Knockout , Morfolinas/farmacologia , Entorpecentes/metabolismo , Medição da Dor/efeitos dos fármacos , Pentazocina/metabolismo , Estimulação Física , Piperazinas/farmacologia , Equilíbrio Postural/efeitos dos fármacos , Pirazóis/farmacologia , Receptores sigma/agonistas , Receptores sigma/genética , Receptor Sigma-1RESUMO
Sigma-1 receptor (sigma(1)R) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. In the present study we investigated the relevance of sigma(1)R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the sigma(1)R gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal-regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous sigma(1)R knockout mice did not differ from wild-type mice. Baseline values obtained in sigma(1)R knockout mice before nerve injury in the plantar, cold-plate and von Frey tests were also indistinguishable from those obtained in wild-type mice. However, cold and mechanical allodynia did not develop in sigma(1)R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking sigma(1)R showed reduced wind-up responses respect to wild-type mice, as evidenced by a reduced number of action potentials induced by trains of C-fiber intensity stimuli. In addition, in contrast to wild-type mice, sigma(1)R knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind-up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify sigma(1)R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to sigma(1)R as a new potential target for drugs designed to alleviate neuropathic pain.
Assuntos
Hiperalgesia/etiologia , Limiar da Dor/fisiologia , Receptores sigma/fisiologia , Neuropatia Ciática/complicações , Neuropatia Ciática/genética , Medula Espinal/fisiopatologia , Análise de Variância , Animais , Biofísica , Modelos Animais de Doenças , Estimulação Elétrica/métodos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/genética , Hiperalgesia/genética , Hiperalgesia/patologia , Masculino , Camundongos , Camundongos Knockout , Medição da Dor , Estimulação Física/efeitos adversos , Estimulação Física/métodos , Tempo de Reação/genética , Receptores sigma/deficiência , Neuropatia Ciática/patologia , Receptor Sigma-1RESUMO
We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that sigma(1) gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,i.pl.), yielding ED(50) (mg/kg) values of 15.80+/-0.93, 29.31+/-1.65 and 40.74+/-7.20, respectively. The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.
Assuntos
Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Nociceptores/metabolismo , Limiar da Dor/fisiologia , Receptores sigma/genética , Medula Espinal/metabolismo , Animais , Anisóis/farmacologia , Capsaicina/farmacologia , DNA/análise , Etilenodiaminas/farmacologia , Feminino , Hiperalgesia/induzido quimicamente , Camundongos , Camundongos Knockout , Morfolinas/farmacologia , Nociceptores/efeitos dos fármacos , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Piperazinas/farmacologia , Reação em Cadeia da Polimerase , Propilaminas/farmacologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Fármacos do Sistema Sensorial/farmacologia , Medula Espinal/efeitos dos fármacos , Receptor Sigma-1RESUMO
We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2mg/kg, i.p., once daily during 5 days) produced long-lasting (2-4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10-14, respectively. Acute subcutaneous treatment with 1 or 3 microg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 microg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 microg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 microg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 microg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.
Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Neuralgia/induzido quimicamente , Neuralgia/prevenção & controle , Paclitaxel/efeitos adversos , Medição da Dor/efeitos dos fármacos , Tetrodotoxina/administração & dosagem , Anestésicos Locais/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , CamundongosRESUMO
Four families of potassium channels with different structures, functional characteristics and pharmacological sensitivity, are distinguished in neurons: voltage-gated (K(v)), calcium-activated (K(Ca)), inward rectifier (K(ir)) and two-pore (K(2P)) K(+) channels. During the last 15 years, numerous studies have demonstrated that the opening of some of these K(+) channels plays an important role in the antinociception induced by agonists of many G-protein-coupled receptors (alpha(2)-adrenoceptors, opioid, GABA(B), muscarinic M(2), adenosine A(1), serotonin 5-HT(1A) and cannabinoid receptors), as well as by other antinociceptive drugs (nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants, etc.) and natural products. Several specific types of K(+) channels are involved in antinociception. The most widely studied are the ATP-sensitive K(+) channels (K(ATP)), members of the K(ir) family, which participate in the antinociception induced by many drugs that activate them in both the central and the peripheral nervous system. The opening of G-protein-regulated inwardly rectifying K(+) channels (GIRK or K(ir)3), K(v)1.1 and two types of K(Ca) channels, the small- and large-conductance calcium-activated K(+) channels (SK and BK channels, respectively), also play a role in the antinociceptive effect of different drugs and natural products. Recently, drugs that open K(+) channels by direct activation (such as openers of neuronal K(v)7 and K(ATP) channels) have been shown to produce antinociception in models of acute and chronic pain, which suggests that other neuronal K(+) channels (e.g. K(v)1.4 channels) may represent an interesting target for the development of new K(+) channel openers with antinociceptive effects.