RESUMEN
The present study investigated the role of metabotropic glutamate receptor subtype 8 (mGluR8) in the dorsal striatum (DS) in modulating thermonociception and rostral ventromedial medulla (RVM) ON and OFF cell activities in conditions of neuropathic pain induced by spared nerve injury (SNI) of the sciatic nerve in rats. The role of DS mGluR8 on mechanical allodynia was also investigated. Intra-DS (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG], a selective mGluR8 agonist, did not modify the activity of the ON and OFF cells in sham-operated rats. In SNI rats, which showed a reduction of the mechanical withdrawal threshold, intra-DS microinjection of (S)-3,4-DCPG inhibited the ongoing and tail flick-evoked activity of the ON cells while increasing the activity of the OFF cells. AZ12216052, a selective mGluR8 positive allosteric modulator (PAM), behaved like (S)-3,4-DCPG in increasing tail flick latency and OFF cell activity and decreasing ON cell activity in SNI rats only but was less potent. VU0155041, a selective mGluR4 PAM, was ineffective in changing thermal nociception and ON and OFF cell activity in both sham-operated and SNI rats. (S)-3,4-DCPG did not change mechanical withdrawal threshold in sham-operated rats but increased it in SNI rats. Furthermore, a decreased level of mGluR8 gene and immunoreactivity, expressed on GABAergic terminals, associated with a protein increase was found in the DS of SNI rats. These results suggest that stimulation of mGluR8 inhibits thermoceptive responses and mechanical allodynia. These effects were associated with inhibition of ON cells and stimulation of OFF cells within RVM.
Asunto(s)
Reacción de Prevención , Cuerpo Estriado/fisiopatología , Bulbo Raquídeo/fisiopatología , Neuralgia/fisiopatología , Nocicepción , Receptores de Glutamato Metabotrópico/metabolismo , Reflejo , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Sensación Térmica , TactoRESUMEN
We showed previously that inhibiting fatty acid amide hydrolase (FAAH), an endocannabinoid degrading enzyme, and transient receptor potential vanilloid type-1 (TRPV1) channels with the same molecule, the naturally occurring N-arachidonoyl-serotonin (AA-5-HT), produces more efficacious anti-nociceptive and anti-hyperalgesic actions than the targeting of FAAH or TRPV1 alone. We also reported the synthesis of some piperazinyl carbamates as "dual" FAAH inhibitors and either antagonists at TRPV1 or agonists/desensitizers of the transient receptor potential ankyrin type-1 (TRPA1) cannel, another target for analgesic drugs. We investigated here if two such compounds, the FAAH/TRPV1 blocker OMDM198 and the FAAH inhibitor/TRPA1 agonist, OMDM202, exert anti-nociceptive actions in the formalin test of pain in mice, and through what mechanism. Both compounds inhibited the second phase of the response to formalin, the effect being maximal at 3 mg/kg, i.p. Antagonism of CB1 or CB2 receptors with AM251 or AM630 (1 mg/kg, i.p.), respectively, reversed this effect. A TRPV1 agonist, palvanil (0.1 mg/kg, i.p.), also reversed the analgesic effect of OMDM198. OMDM202 action was also antagonized by a per se inactive dose of the selective TRPA1 blocker, AP-18 (0.05 mg/kg, i.p.), but not by a TRPV1 antagonist. AP-18 at higher doses (0.1-0.2 mg/kg) inhibited both the first and second phase of the formalin response. The effects of OMDM198 and OMDM202 were accompanied by elevation of anandamide levels in the spinal cord. OMDM198 (0.1-5.0 mg/kg, i.p.) also reversed carrageenan-induced oedema and thermal hyperalgesia in mice with efficacy similar to that of AA-5-HT. These data suggest that "dual" fatty acid amide hydrolase and transient receptor potential channel modulators should be clinically evaluated as novel analgesics.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/uso terapéutico , Carbamatos/uso terapéutico , Dolor/tratamiento farmacológico , Analgésicos/química , Animales , Ácidos Araquidónicos/análisis , Ácidos Araquidónicos/metabolismo , Carbamatos/química , Edema/tratamiento farmacológico , Edema/enzimología , Edema/metabolismo , Endocannabinoides/análisis , Endocannabinoides/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/enzimología , Dolor/metabolismo , Dimensión del Dolor/efectos de los fármacos , Alcamidas Poliinsaturadas/análisis , Alcamidas Poliinsaturadas/metabolismo , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/agonistasRESUMEN
BACKGROUND: Salvinorin A (SA), the main active component of Salvia Divinorum, is a non-nitrogenous kappa opioid receptor (KOR) agonist. It has been shown to reduce acute pain and to exert potent antinflammatory effects. This study assesses the effects and the mode of action of SA on formalin-induced persistent pain in mice. Specifically, the SA effects on long-term behavioural dysfuctions and changes in neuronal activity occurring at spinal level, after single peripheral formalin injection, have been investigated. Moreover, the involvement of microglial and glial cells in formalin-induced chronic pain condition and in SA-mediated effects has been evaluated. RESULTS: Formalin induced a significant decrease of mechanical withdrawal threshold at the injected and contralateral paw as well as an increase in the duration and frequency, and a rapid decrease in the onset of evoked activity of the nociceptive neurons 7 days after formalin injection. SA daily treatment significantly reduced mechanical allodynia in KOR and cannabinoid receptor 1 (CB1R) sensitive manner. SA treatment also normalized the spinal evoked activity. SA significantly reduced the formalin-mediated microglia and astrocytes activation and modulated pro and anti-inflammatory mediators in the spinal cord. CONCLUSION: SA is effective in reducing formalin-induced mechanical allodynia and spinal neuronal hyperactivity. Our findings suggest that SA reduces glial activation and contributes in the establishment of dysfunctions associated with chronic pain with mechanisms involving KOR and CB1R. SA may provide a new lead compound for developing anti-allodynic agents via KOR and CB1R activation.
Asunto(s)
Antiinflamatorios/uso terapéutico , Diterpenos de Tipo Clerodano/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Animales , Formaldehído/toxicidad , Masculino , Ratones , Ratones Endogámicos ICR , Nociceptores/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats. RESULTS: The effect of N-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively. CONCLUSION: These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Mononeuropatías/enzimología , Corteza Prefrontal/enzimología , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiopatología , Animales , Ácidos Araquidónicos/administración & dosificación , Ácidos Araquidónicos/farmacología , Benzamidas/administración & dosificación , Benzamidas/farmacología , Carbamatos/administración & dosificación , Carbamatos/farmacología , Estimulación Eléctrica , Electrodos , Fenómenos Electrofisiológicos/efectos de los fármacos , Masculino , Microdiálisis , Microinyecciones , Mononeuropatías/patología , Mononeuropatías/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Nociceptores/metabolismo , Piperidinas/administración & dosificación , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Corteza Prefrontal/fisiopatología , Pirazoles/administración & dosificación , Pirazoles/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Serotonina/administración & dosificación , Serotonina/análogos & derivados , Serotonina/farmacología , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
N-acyl-vanillamide (NAVAM) analogues of the natural pungent principle of capsicum, capsaicin, were developed several years ago as potential non-pungent analgesic compounds. N-oleoyl-vanillamide (olvanil) and N-arachidonoy-vanillamide (arvanil), in particular, were described in several publications and patents to behave as potent anti-hyperalgesic compounds in experimental models of chronic and inflammatory pain, and to activate both "capsaicin receptors", i.e. the transient receptor potential of vanilloid type-1 (TRPV1) channel, and, either directly or indirectly, cannabinoid receptors of type-1. Here we report the biochemical and pharmacological characterization of a so far neglected NAVAM, N-palmitoyl-vanillamide (palvanil), and propose its possible use instead of capsaicin, as a possible topical analgesic. Palvanil exhibited a kinetics of activation of human recombinant TRPV1-mediated intracellular calcium elevation significantly slower than that of capsaicin (t(1/2)=21s and 8s, respectively at 1µM). Slow kinetics of TRPV1 agonists were previously found to be associated with stronger potencies as TRPV1 desensitizing agents, which in turn are usually associated with lower pungency and stronger anti-hyperalgesic activity. Accordingly, palvanil desensitized the human recombinant TRPV1 to the effect of capsaicin (10nM) with significantly higher potency than capsaicin (IC(50)=0.8nM and 3.8nM, respectively), this effect reaching its maximum more rapidly (50 and 250min, respectively). Palvanil was also more potent than capsaicin at desensitizing the stimulatory effect of TRPV1 by low pH together with anandamide, which mimics conditions occurring during inflammation. In the eye-wiping assay carried out in mice, palvanil was not pungent and instead caused a strong and long-lasting inhibition of capsaicin-induced eye-wiping. Finally, intraplantar palvanil inhibited the second phase of the nociceptive response to formalin in mice. In conclusion, palvanil appears to be a non-pungent analogue of capsaicin with stronger desensitizing effects on TRPV1 and hence potentially higher anti-hyperalgesic activity.
Asunto(s)
Analgésicos/uso terapéutico , Capsaicina/análogos & derivados , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/metabolismo , Administración Tópica , Analgésicos/farmacología , Animales , Ácidos Araquidónicos/farmacología , Calcio/metabolismo , Capsaicina/farmacología , Capsaicina/uso terapéutico , Línea Celular , Endocannabinoides , Ojo/efectos de los fármacos , Humanos , Masculino , Ratones , Alcamidas Poliinsaturadas/farmacologíaRESUMEN
OBJECTIVES: Paracetamol is converted to an active metabolite AM404 via fatty acid amide hydrolase (FAAH). The aim of the present study was to ascertain whether a FAAH inhibitor URB597 antagonizes paracetamol analgesic activity (and to asses by this way the role of FAAH in analgesic activity of paracetamol). METHODS: The interaction between a FAAH inhibitor URB597 and paracetamol was investigated in the writhing test in mice using an isobolographic analysis. RESULTS: URB597 or paracetamol alone and in combinations produced dose-dependent antinociceptive effects. ED50 values were estimated for the individual drugs and an isobologram was constructed. The observed ED50 value for the URB57-paracetamol combination was 0.097 (0.062-0.247) mg/kg. This value did not differ significantly from the theoretical additive ED50 value for the URB597-paracetamol combination which was 0.108 (0.059-0.198) mg/kg. Thus, inhibition of FAAH by URB597 was not followed by the lack of analgesic activity in paracetamol. CONCLUSION: The present results suggest that the analgesic activity of paracetamol is not dependent solely on FAAH metabolic conversion to AM404 and that paracetamol exerts analgesic activity also by additional mechanisms.
Asunto(s)
Acetaminofén/farmacología , Amidohidrolasas/antagonistas & inhibidores , Benzamidas/farmacología , Carbamatos/farmacología , Dimensión del Dolor/efectos de los fármacos , Analgésicos no Narcóticos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Modelos Lineales , Masculino , RatonesRESUMEN
Plastic changes in the amygdala and limbic cortex networks have been widely shown in chronic pain. We have here investigated the role of group I metabotropic glutamate receptors (mGluRs) in the basolateral amygdala (BLA) pre-infra-limbic (PL-IL) divisions of the medial prefrontal cortex (mPFC) neuron connections after carrageenan-induced inflammatory pain in the rat. Intra-plantar injection of carrageenan decreased either spontaneous or mechanically/electrically evoked activity of PL cortex pyramidal neurons which responded with excitation in a way prevented by CPCOOEt, a selective mGluR1 antagonist, though not by MPEP, a selective mGluR5 antagonist. Accordingly, intra-BLA microinjection of DHPG, a group I mGluR agonist, caused PL cortex neuron activity depression, antagonized by CPCCOEt. CPCOOEt, but not MPEP, reduced also carrageenan-induced mechanical allodynia. The PL cortex cell deactivation in inflammatory pain condition was associated with increased GABA (conversely glutamate was decreased) in the PL/IL cortex. The local application of bicuculline, a GABA(A) receptor selective antagonist, reduced mechanical allodynia. An over-expression of mGluR1, but not mGluR5, have been observed in the PL-IL cortex after inflammatory pain suggesting an increased mGluR1-dependent cross-talk among BLA and IL-PL cortex neurons in inflammatory pain conditions. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Asunto(s)
Amígdala del Cerebelo/fisiología , Dolor/fisiopatología , Corteza Prefrontal/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Bicuculina/farmacología , Carragenina , Cromonas/administración & dosificación , Cromonas/farmacología , Modelos Animales de Enfermedad , Estimulación Eléctrica/métodos , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Formaldehído/farmacología , Antagonistas del GABA/farmacología , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Glicina/administración & dosificación , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Estimulación Física/métodos , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Piridinas/administración & dosificación , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/biosíntesis , Resorcinoles/administración & dosificación , Resorcinoles/farmacologíaRESUMEN
Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.
Asunto(s)
4-Quinolonas/química , Ácidos Carboxílicos/química , Simulación por Computador , Receptor Cannabinoide CB2/agonistas , Animales , Células CHO , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Cricetinae , Cricetulus , Humanos , Ligandos , Lípidos/química , Ratones , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Solubilidad , Relación Estructura-ActividadRESUMEN
The hallucinogenic compound, salvinorin A, is a potent κ-opioid receptor (KOR) agonist. However, other target(s) than the KOR, such as the cannabinoid CB1 receptor, have been proposed to explain its multiple pharmacological actions. Here, we have evaluated the effect of salvinorin A in lipopolysaccharide (LPS)-stimulated macrophages as well as in models of inflammation in vivo. Salvinorin A (0.1-10 pM) reduced LPS-stimulated nitrite, TNF-α and IL-10 (but not IL-1ß) levels as well as iNOS (but not COX-2) LPS-induced hyperexpression. The effect of salvinorin A on nitrite levels was reverted by the opioid antagonist naloxone, the KOR antagonist nor-binaltorphimine and by the CB1 antagonist rimonabant Salvinorin A also prevented KOR and CB1 hyperexpression induced by LPS. In vivo, salvinorin A reduced the LPS- and the carrageenan-induced paw oedema and formalin-induced inflammatory pain, in a nor-binaltorphimine and rimonabant-sensitive manner. It is concluded that salvinorin A-via KORs and CB1 receptors-exerts ultrapotent actions on macrophages and also shows moderate antinflammatory effects in vivo.
Asunto(s)
Antiinflamatorios/farmacología , Diterpenos de Tipo Clerodano/farmacología , Macrófagos/efectos de los fármacos , Salvia/química , Animales , Antiinflamatorios/toxicidad , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Diterpenos de Tipo Clerodano/toxicidad , Edema/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismoRESUMEN
This study has investigated whether the galactosyl ester prodrug of N(ω)-nitro-L-arginine (NAGAL), shows enhanced analgesic efficacy in healthy mice and in models of visceral and neuropathic pain: the writhing test and the spared nerve injury (SNI), respectively. NAGAL was compared to methyl ester pro-drug of N(ω)-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED(50) value, along with the 95% confidence limit (CL) was 3.82 (1.77-6.04) mg/kg for NAGAL and, 36.75 (20.07-68.37) mg/kg for L-NAME. Notably, NAGAL elicited a greater anti-allodynic effect than L-NAME did in neuropathic mice. Biomolecular and morphological studies revealed that spared nerve injury increased the expressions of pro-inflammatory enzymes (caspase-1) and two glial cell biomarkers: integrin alpha M (ITGAM) and glial fibrillary acidic protein (GFAP) in the spinal cord. Finally, GLUT-3, an isoform of the hexose transporters capable to bind NAGAL and inducible NOS (iNOS), were found to be over-expressed in the activated astrocytes of the spinal cord of neuropathic mice. NAGAL administration normalized expression levels of these biomarkers. NAGAL showed a greater efficacy in inhibiting visceral pain and allodynia than L-NAME possibly by a greater cell permeation through the hexose transporter which is highly over-expressed by activated glia.
Asunto(s)
Galactosa/metabolismo , Hiperalgesia/tratamiento farmacológico , Neuralgia/patología , Neuroglía/efectos de los fármacos , Nitroarginina/metabolismo , Nitroarginina/farmacología , Profármacos/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Presión Sanguínea/efectos de los fármacos , Caspasas/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 3/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , NG-Nitroarginina Metil Éster/farmacología , Neuralgia/metabolismo , Neuralgia/fisiopatología , Neuroglía/citología , Neuroglía/metabolismo , Neuroglía/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitroarginina/uso terapéutico , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/fisiopatología , Factores de TiempoRESUMEN
Experimental evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy derivative 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compound, evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.
Asunto(s)
4-Quinolonas/farmacología , Adamantano/análogos & derivados , Quinolonas/farmacología , Receptor Cannabinoide CB2/metabolismo , 4-Quinolonas/síntesis química , 4-Quinolonas/metabolismo , Adamantano/síntesis química , Adamantano/metabolismo , Adamantano/farmacología , Analgésicos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Células Hep G2 , Humanos , Ligandos , Ratones , Quinolonas/síntesis química , Quinolonas/metabolismo , Ratas , Receptor Cannabinoide CB2/efectos de los fármacosRESUMEN
The 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid, DM2, exerts anti-absence activity and blocks Cav3.1 channel, a T-type voltage-dependent Ca(2+) channel subtype, in vitro. The current study investigated the effect of intra-ventrolateral periaqueductal grey (VLPAG) administration of DM2 on formalin-induced nocifensive responses in rats. In addition, the effect of intra-VLPAG microinjection of DM2 on the ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) cell population was also investigated. Formalin was injected subcutaneously into the dorsal surface of the hind paws of awake rats. We found that DM2 reduced nocifensive responses in the late phase of the formalin test. Moreover, in the RVM, the intra-VLPAG microinjection of DM2 reduced the ongoing and tail flick-related activity of the nociceptive ON cells, whereas it increased the ongoing activity and reduced the tail flick-induced pause of the antinociceptive OFF cells, consistent with antinociception. Behavioural and electrophysiological effects were reproduced by intra-VLPAG microinjection of ethosuximide, a conventional T-type Ca(2+) channel blocker. Finally, DM2 administration did not produce any adverse cardiovascular effects as blood pressure and heart rate remained unchanged. In conclusion, DM2 plays an analgesic role in vivo and changes RVM cell activity, consistent with antinociception. These effects were even more potent than those elicited by ethosuximide treatments.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Bulbo Raquídeo/citología , Neuronas/efectos de los fármacos , Dolor/tratamiento farmacológico , Piridinas/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Anticonvulsivantes/farmacología , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Etosuximida/farmacología , Formaldehído/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones/métodos , Neuronas/fisiología , Dolor/inducido químicamente , Dimensión del Dolor/métodos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Factores de TiempoRESUMEN
A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki>100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.