RESUMO
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
Assuntos
Analgésicos/farmacologia , Benzoxazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Sulfonamidas/farmacologia , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/química , Disponibilidade Biológica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído/administração & dosagem , Humanos , Camundongos , Estrutura Molecular , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Dor/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
Assuntos
Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Nitrogênio/química , Dor/tratamento farmacológico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
This study aims to identify fMRI signatures of nociceptive processing in whole brain of anesthetized rats during noxious electrical stimulation (NES) and noxious mechanical stimulation (NMS) of paw. Activation patterns for NES were mapped with blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) fMRI, respectively, to investigate the spatially-dependent hemodynamic responses during nociception processing. A systematic evaluation of fMRI responses to varying frequencies of electrical stimulus was carried out to optimize the NES protocol. Both BOLD and CBV fMRI showed widespread activations, but with different spatial characteristics. While BOLD and CBV showed well-localized activations in ipsilateral dorsal column nucleus, contralateral primary somatosensory cortex (S1), and bilateral caudate putamen (CPu), CBV fMRI showed additional bilateral activations in the regions of pons, midbrain and thalamus compared to BOLD fMRI. CBV fMRI that offers higher sensitivity compared to BOLD was then used to compare the nociception processing during NES and NMS in the same animal. The activations in most regions were similar. In the medulla, however, NES induced a robust activation in the ipsilateral dorsal column nucleus while NMS showed no activation. This study demonstrates that (1) the hemodynamic response to nociception is spatial-dependent; (2) the widespread activations during nociception in CBV fMRI are similar to what have been observed in (14)C-2-deoxyglucose (2DG) autoradiography and PET; (3) the bilateral activations in the brain originate from the divergence of neural responses at supraspinal level; and (4) the similarity of activation patterns suggests that nociceptive processing in rats is similar during NES and NMS.
Assuntos
Encéfalo/fisiopatologia , Circulação Cerebrovascular , Estimulação Elétrica , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Dor/fisiopatologia , Estimulação Física , Animais , Velocidade do Fluxo Sanguíneo , Volume Sanguíneo , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Amidinas/química , Amilorida/química , Animais , Proteínas do Tecido Nervoso/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
Assuntos
Amidas/química , Analgésicos/química , Quinolinas/química , Receptor CB2 de Canabinoide/agonistas , Amidas/síntese química , Amidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Dor/tratamento farmacológico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Assuntos
Analgésicos/química , Piridinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Piridinas/síntese química , Piridinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologiaRESUMO
BACKGROUND AND PURPOSE: Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid-sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons. EXPERIMENTAL APPROACH: To examine the contribution of ASIC3 to the development and maintenance of muscle pain and inflammatory pain, we studied the in vivo efficacy of a selective ASIC3 inhibitor, APETx2, in rats. KEY RESULTS: Administration of APETx2 into the gastrocnemius muscle prior to the administration of low pH saline prevented the development of mechanical hypersensitivity, whereas APETx2 administration following low-pH saline was ineffective in reversing hypersensitivity. The prevention of mechanical hypersensitivity produced by acid administration was observed whether APETx2 was applied via i.m. or i.t. routes. In the complete Freund's adjuvant (CFA) inflammatory pain model, local administration of APETx2 resulted in a potent and complete reversal of established mechanical hypersensitivity, whereas i.t. application of APETx2 was ineffective. CONCLUSIONS AND IMPLICATIONS: ASIC3 contributed to the development of mechanical hypersensitivity in the acid-induced muscle pain model, whereas ASIC3 contributed to the maintenance of mechanical hypersensitivity in the CFA inflammatory pain model. The contribution of ASIC3 to established hypersensitivity associated with inflammation suggests that this channel may be an effective analgesic target for inflammatory pain states.
Assuntos
Venenos de Cnidários/farmacologia , Inflamação/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Dor/fisiopatologia , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Células CHO , Venenos de Cnidários/administração & dosagem , Cricetinae , Cricetulus , Modelos Animais de Doenças , Adjuvante de Freund/toxicidade , Concentração de Íons de Hidrogênio , Inflamação/tratamento farmacológico , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio/toxicidadeRESUMO
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/síntese química , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Canais Iônicos Sensíveis a Ácido/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , Fenômenos Eletrofisiológicos , Adjuvante de Freund , Iodoacetatos , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Estimulação Física , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amidinas/química , Química Farmacêutica/métodos , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Animais , Desenho de Fármacos , Eletrofisiologia , Indóis/química , Concentração Inibidora 50 , Canais Iônicos/química , Masculino , Modelos Químicos , Naproxeno/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Previous studies have suggested a role for both CB1 and CB2 cannabinoid receptors in modulation of nociception. To further examine the role of CB1 and CB2 receptors in antinociception, we evaluated the efficacy of the non-selective cannabinoid receptor agonist, CP 55,940, in models of acute, inflammatory, and neuropathic pain in control mice, CB1 receptor knockout mice, and CB2 receptor knockout mice. In control C57BL/6 mice, administration of CP 55,940 (0.03-0.3 mg/kg, i.p.) reversed complete Freund's adjuvant-induced tactile allodynia, reversed tactile allodynia in the spinal nerve ligation model and inhibited the noxious heat-evoked tail withdrawal response. In addition to its antinociceptive effects, CP 55,940 produced an impairment of motor coordination in the rotarod test. The antinociceptive effects produced by CP 55,940 and associated motor deficits were found to be completely abolished in CB1 receptor knockout mice. In contrast, the antinociceptive effects of CP 55,940 in all pain models were fully retained in CB2 receptor knockout mice, along with the associated motor deficits. The results suggest that the antinociceptive effects of CP 55,940 in models of acute and persistent pain, along with the associated motor deficits, are mediated by CB1 receptors, and likely not CB2 receptors.
Assuntos
Analgésicos/farmacologia , Cicloexanóis/farmacologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Analgésicos/administração & dosagem , Animais , Cicloexanóis/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Dor/induzido quimicamente , Medição da Dor , Estimulação Física , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Nervos Espinhais/lesõesRESUMO
A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amilorida/análogos & derivados , Química Farmacêutica/métodos , Proteínas do Tecido Nervoso/química , Dor/tratamento farmacológico , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Acidose , Amilorida/química , Aminas/química , Animais , Desenho de Fármacos , Eletrofisiologia , Concentração Inibidora 50 , Masculino , Modelos Químicos , Pirazinas/química , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The sodium channel blocker amitriptyline has been shown to inhibit ectopic discharge in injured nerves. In the present study, we characterized ectopic discharges of afferent fibers following L5/L6 spinal nerve ligation (SNL) by their electrophysiological properties and sensitivities to inhibition by amitriptyline in the decentralized L5 dorsal root in SNL rats. METHODS: Rats exhibiting withdrawal thresholds <4.0 g after SNL were selected for the present study. After laminectomy in pentobarbital-anesthetized rats, the L5 dorsal root was decentralized close to its entry to the spinal cord, and the spontaneous activities of single units were recorded peripherally before and after IV administration of amitriptyline. The mean frequency of afferent fiber activity and instantaneous frequency were measured. RESULTS: The spontaneous activities of afferent fibers in naïve rats had high frequency (35.23 +/- 6.63 Hz) and pattern discharge based on their instantaneous frequencies and interspike interval distributions. In rats that had received SNL, afferent fibers exhibited spontaneous discharge (mean of 11.05 +/- 3.66 Hz) with an irregular discharge pattern or short bursting activity in some cases. Only 5/13 (38%) afferent fibers from naïve rats showed reduced spontaneous activities after amitriptyline (2 mg/kg, IV), whereas amitriptyline significantly inhibited ectopic discharge in 13/18 (72%) afferent fibers from SNL rats (ID(50) = 1.66 +/- 0.17 mg/kg). Furthermore, the greatest inhibitory effect of amitriptyline was consistently observed on those afferent fibers exhibiting low frequency (<20 Hz) and/or bursting discharge. CONCLUSION: These results provide direct evidence that amitriptyline, which is used clinically for the treatment of neuropathic pain, selectively inhibits ectopic discharge of low frequency and bursting discharge in the rat neuropathic pain model.
Assuntos
Amitriptilina/farmacologia , Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Neurônios Aferentes/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Raízes Nervosas Espinhais/efeitos dos fármacos , Potenciais de Ação , Amitriptilina/administração & dosagem , Analgésicos/administração & dosagem , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intravenosas , Laminectomia , Ligadura , Vértebras Lombares , Masculino , Neuralgia/fisiopatologia , Neurônios Aferentes/metabolismo , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/administração & dosagem , Raízes Nervosas Espinhais/fisiopatologia , Raízes Nervosas Espinhais/cirurgia , Fatores de TempoRESUMO
BACKGROUND: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain. RESULTS: The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain. CONCLUSION: Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
Assuntos
Acetanilidas/farmacologia , Analgésicos/farmacologia , Canais de Cálcio/fisiologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/fisiologia , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Purinas/farmacologia , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/fisiologia , Animais , Anquirinas , Linhagem Celular , Modelos Animais de Doenças , Humanos , Inflamação , Masculino , Neuralgia/etiologia , Neuralgia/patologia , Dor/etiologia , Dor/patologia , Ratos , Ratos Sprague-Dawley , Canal de Cátion TRPA1 , Canais de Cátion TRPCRESUMO
Spinal cord fMRI is a useful tool for studying spinal mechanisms of pain, hence for analgesic drug development. Its technical feasibility in both humans and rats has been demonstrated. This study investigates the reproducibility, robustness, and spatial accuracy of fMRI of lumbar spinal cord activation due to transcutaneous noxious and non-noxious electrical stimulation of the hindpaw in alpha-chloralose-anesthetized rats. Blood oxygenation level-dependent (BOLD) and blood volume-weighted fMRI data were acquired without and with intravenous injection of ultra small superparamagnetic iron oxide particles (USPIO), respectively, using a gradient echo (GE) echo planar imaging (EPI) technique at 4.7 T. Neuronal activation in the spinal cord induced by noxious stimulation to the hindpaw (2 ms wide, 5 mA amplitude, known to activate C-fibers) can be robustly detected by both fMRI techniques with excellent reproducibility and peaked at the stimulus frequency of 40 Hz. However, both fMRI techniques were not sensitive to neuronal activation in spinal cord induced by non-noxious stimulation (0.3 ms, 1.5 mA, known only to activate A-fibers). Spatially, the fMRI signal extended approximately 5 mm in the longitudinal direction, covering L(3)-L(5) segments. In the cross-sectional direction, the highest signal change of blood volume-weighted fMRI was in the middle of the ipsilateral dorsal horn, which roughly corresponds to laminae V and VI, while the highest signal change of BOLD fMRI was in the ipsilateral dorsal surface. This study demonstrates that spinal cord fMRI can be performed in anesthetized rats reliably and reproducibly offering it as a potential tool for analgesic drug discovery.
Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Oxigênio/sangue , Dor/patologia , Medula Espinal/patologia , Animais , Meios de Contraste , Interpretação Estatística de Dados , Imagem Ecoplanar , Estimulação Elétrica , Compostos Férricos , Pé , Membro Posterior , Magnetismo , Masculino , Ratos , Ratos WistarRESUMO
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Assuntos
Acetamidas/síntese química , Amidas/síntese química , Compostos de Aminobifenil/síntese química , Benzoatos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Ciclopropanos/síntese química , Medula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/farmacocinética , Benzoatos/farmacologia , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Cannabinoid receptor agonists have previously been shown to produce antinociceptive effects in rodent models of inflammatory pain. In the present study, we characterized responses of spinal dorsal horn neurons receiving sensory input from the hind paw in rats that had received intraplantar injection of complete Freund's adjuvant (CFA), and examined effects of the nonselective CB1/2 receptor agonist CP55,940 on spinal neuron responses. Systemic (i.v.) administration of CP55,940 failed to attenuate responses of dorsal horn neurons to noxious mechanical stimulation in naïve rats, but significantly reduced responses in CFA-inflamed rats to 25.78+/-13.7% of vehicle control at a cumulative dose of 0.8 mg/kg (ID50=0.28+/-0.02 mg/kg). Additionally, local administration of CP55,940 (10 microM) to the spinal cord reduced responses of mechanosensory dorsal horn neurons in CFA-inflamed rats to 67.15+/-7.1% of vehicle control. The inhibitory action of CP55,940 on spinal dorsal horn neurons in CFA-inflamed rats was mediated by CB1 receptors since local pretreatment with the CB1 receptor antagonist AM251 (10 microM) blocked this effect, while the CB2 receptor antagonist AM630 (10 microM) was ineffective. Our results suggest that following inflammation, the inhibition of spinal nociceptive transmission by CP55,940 is mediated in part by spinal CB1 receptors, and not spinal CB2 receptors.
Assuntos
Cicloexanos/farmacologia , Inflamação/metabolismo , Mecanorreceptores/fisiologia , Dor/metabolismo , Fenóis/farmacologia , Células do Corno Posterior/metabolismo , Receptores de Canabinoides/metabolismo , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Moduladores de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Doença Crônica , Cicloexanóis , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Mecanorreceptores/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Dor/tratamento farmacológico , Dor/fisiopatologia , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides/efeitos dos fármacosRESUMO
We investigated whether the metabotropic glutamate receptor subtype 5 (mGluR5) selective antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has direct effects on primary afferent fiber responses to noxious mechanical stimulation following inflammation. Mechanosensory primary afferent fibers innervating the hind paw were recorded in naïve and complete Freunds adjuvant (CFA) inflamed rats. Following intraplantar injection of CFA, afferent fibers showed property changes including expanded receptive fields, burst firing with fast adaptive mechanical responses and a higher incidence of cold and/or heat sensitivities compared to naïve rats. In eight afferent fibers tested following i.v. administration of MPEP, seven fibers showed significantly reduced responses to noxious mechanical stimulation. At a cumulative dose of 10 mg/kg, MPEP inhibited afferent responses to 32.66+/-11.48% of control. The mean ID50 value of MPEP was 6.49+/-0.43 mg/kg. In contrast to its inhibitory action in the CFA model, i.v. administration of MPEP produced only a mild reduction of mechanical responses in 3 fibers out of 11 in naïve rats. These results provide direct functional evidence that blockade of peripheral mGluR5 receptors inhibits nociceptive transmission and support previous studies demonstrating a peripheral site of action associated with the antinociceptive effect of MPEP following inflammation.
Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Membro Posterior/inervação , Inflamação/tratamento farmacológico , Mecanorreceptores/fisiopatologia , Dor/tratamento farmacológico , Piridinas/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/complicações , Mecanorreceptores/efeitos dos fármacos , Dor/etiologia , Medição da Dor/métodos , Estimulação Física/métodos , RatosRESUMO
The present study was designed to determine the contribution of N-type, P/Q-type and L-type calcium channels in the rostral ventromedial medulla to tactile allodynia following peripheral nerve injury. L5/L6 spinal nerve ligation in rats produced tactile allodynia, which was dose-dependently inhibited by intrarostral ventromedial medulla microinjection of the N-type calcium channel antagonist omega-conotoxin MVIIA. Similarly, intrarostral ventromedial medulla microinjection of the P/Q-type calcium channel antagonist omega-agatoxin IVA inhibited spinal nerve ligation-induced tactile allodynia, whereas intrarostral ventromedial medulla microinjection of the L-type calcium channel antagonist nimodipine had no effect. These results demonstrate that N-type and P/Q-type calcium channels in the rostral ventromedial medulla contribute to tactile allodynia following peripheral neuropathy, likely via neurotransmitter-mediated activation of descending facilitatory systems from the rostral ventromedial medulla.
Assuntos
Canais de Cálcio Tipo N/fisiologia , Bulbo/fisiologia , Neuralgia/fisiopatologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Hiperalgesia/fisiopatologia , Ligadura , Masculino , Bulbo/efeitos dos fármacos , Microinjeções , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/fisiologia , Tato , ômega-Agatoxina IVA/farmacologia , ômega-Conotoxinas/farmacologiaRESUMO
In the current study, a possible interaction between spinal cord dorsal horn cannabinoid and mGlu5 receptors was evaluated in rats with a peripheral nerve injury. Following unilateral loose ligation of a sciatic nerve, rats developed decreased withdrawal thresholds to noxious pressure (mechanical hyperalgesia) of the ligated but not the unoperated contralateral hind paw. Systemic (subcutaneous) injection of synthetic cannabinoid agonist WIN55,212-2 increased withdrawal thresholds of both the ligated and the unoperated hind paw. Systemic injection of 2-methyl-6-(phenylethynyl)pyradine (MPEP), an antagonist selective for the mGlu5 receptor, did not alter the antinociceptive and antihyperalgesic effects of systemic WIN55,212-2. Intrathecal (i.t.) injection of WIN55,212-2 increased thresholds of the ligated but not the unoperated hind paw. Intrathecal injection of MPEP reversed the antihyperalgesic effect of i.t. WIN55,212-2. Neither systemic nor i.t. injection of MPEP alone altered withdrawal thresholds. These data suggest that the antihyperalgesic effect of WIN55,212-2 is mediated through an interaction with spinal mGlu5 receptors.