RESUMEN
The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.
Asunto(s)
Mialgia/tratamiento farmacológico , Receptores de Cannabinoides/fisiología , Receptores Opioides/fisiología , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Carragenina , Cinamatos/farmacología , Endocannabinoides/antagonistas & inhibidores , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/psicología , Masculino , Monoacilglicerol Lipasas/antagonistas & inhibidores , Derivados de la Morfina/farmacología , Mialgia/inducido químicamente , Mialgia/psicología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dimensión del Dolor/efectos de los fármacos , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores de Cannabinoides/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacosRESUMEN
Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.
Asunto(s)
Síntomas Afectivos/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Endocannabinoides/metabolismo , Esquizofrenia/metabolismo , Síntomas Afectivos/inducido químicamente , Animales , Ácidos Araquidónicos/agonistas , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Ácidos Araquidónicos/uso terapéutico , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Disfunción Cognitiva/inducido químicamente , Endocannabinoides/agonistas , Endocannabinoides/antagonistas & inhibidores , Masculino , Alcamidas Poliinsaturadas/agonistas , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Esquizofrenia/inducido químicamente , Esquizofrenia/prevención & controlRESUMEN
The present study investigated the effects of systemic or intra-dorsolateral periaqueductal gray (dlPAG) administration of CB1 agonists on behavioural changes induced in rats by predator (a live cat) exposure, a model of panic responses. Since nitric oxide (NO) and cannabinoid neurotransmission are proposed to interact in the dlPAG to modulate defensive responses, we also investigated if NO is involved in the biphasic effects of anandamide (AEA) injected into the dlPAG. The results showed that systemic administration of WIN55,212-2 or intra-dlPAG AEA attenuated the defensive behaviours caused by cat exposure. Both compounds produced biphasic curves. The cannabinoid receptor type 1 (CB1) antagonist AM251 prevented the panicolytic effect of AEA whereas a neuronal NOS inhibitor turned the ineffective high dose of AEA into an effective one. These results suggest that modulation of the cannabinoid system could be a target in the treatment of panic disorders. However, the biphasic effects of these compounds could limit their therapeutic potential.
Asunto(s)
Miedo/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiología , Conducta Predatoria , Animales , Ácidos Araquidónicos/administración & dosificación , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/farmacología , Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Gatos , Relación Dosis-Respuesta a Droga , Endocannabinoides/administración & dosificación , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/farmacología , Inhibidores Enzimáticos/farmacología , Miedo/fisiología , Masculino , Microinyecciones , Morfolinas/farmacología , Naftalenos/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Ornitina/análogos & derivados , Ornitina/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/administración & dosificación , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/farmacología , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismoRESUMEN
BACKGROUND: Cannabinoid agonists induce norepinephrine release in central, spinal, and peripheral sites. Previous studies suggest an interaction between the cannabinoid and adrenergic systems on antinociception. In this study, we sought to verify whether the CB1 and CB2 cannabinoid receptor agonists anandamide and N-palmitoyl-ethanolamine (PEA), respectively, are able to induce peripheral antinociception via an adrenergic mechanism. METHODS: All drugs were administered locally into the right hindpaw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2 (2 µg). RESULTS: Anandamide, 12.5 ng/paw, 25 ng/paw, and 50 ng/paw elicited a local peripheral antinociceptive effect that was antagonized by CB1 cannabinoid receptor antagonist AM251, 20 µg/paw, 40 µg/paw, and 80 µg/paw, but not by CB2 cannabinoid receptor antagonist AM630, 100 µg/paw. PEA, 5 µg/paw, 10 µg/paw, and 20 µg/paw, elicited a local peripheral antinociceptive effect that was antagonized by AM630, 25 µg/paw, 50 µg/paw, and 100 µg/paw, but not by AM251, 80 µg/paw. Antinociception induced by anandamide or PEA was antagonized by the nonselective α2 adrenoceptor antagonist yohimbine, 05 µg/paw, 10 µg/paw, and 20 µg/paw, and by the selective α2C adrenoceptor antagonist rauwolscine, 10 µg/paw, 15 µg/paw, and 20 µg/paw, but not by the selective antagonists for α2A, α2B, and α2D adrenoceptor subtypes, 20 µg/paw. The antinociceptive effect of the cannabinoids was also antagonized by the nonselective α1 adrenoceptor antagonist prazosin, 0.5 µg/paw, 1 µg/paw, and 2 µg/paw, and by the nonselective ß adrenoceptor antagonist propranolol, 150 ng/paw, 300 ng/paw, and 600 ng/paw. Guanethidine, which depletes peripheral sympathomimetic amines (30 mg/kg/animal, once a day for 3 days), restored approximately 70% the anandamide-induced and PEA-induced peripheral antinociception. Furthermore, acute injection of the norepinephrine reuptake inhibitor reboxetine, 30 µg/paw, intensified the antinociceptive effects of low-dose anandamide, 12.5 ng/paw, and PEA, 5 µg/paw. CONCLUSIONS: This study provides evidence that anandamide and PEA induce peripheral antinociception activating CB1 and CB2 cannabinoid receptors, respectively, stimulating an endogenous norepinephrine release that activates peripheral adrenoceptors inducing antinociception.
Asunto(s)
Analgésicos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Norepinefrina/fisiología , Nervios Periféricos/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Sistema Nervioso Simpático/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas Adrenérgicos beta/farmacología , Amidas , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/farmacología , Dinoprostona , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/farmacología , Etanolaminas/antagonistas & inhibidores , Etanolaminas/farmacología , Masculino , Morfolinas/farmacología , Dimensión del Dolor/efectos de los fármacos , Ácidos Palmíticos/antagonistas & inhibidores , Ácidos Palmíticos/farmacología , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/farmacología , Prazosina/farmacología , Propranolol/farmacología , Ratas , Ratas Wistar , Reboxetina , Yohimbina/farmacologíaRESUMEN
There are contradictory results concerning the effects of systemic injections of cannabinoid agonists in anxiety-induced behavioral changes. Direct drug administration into brain structures related to defensive responses could help to clarify the role of cannabinoids in these changes. Activation of cannabinoid CB(1) receptors in the dorsolateral periaqueductal gray induces anxiolytic-like effects in the elevated plus maze. The aim of this work was to verify if facilitation of endocannabinoid-mediated neurotransmission in this region would also produce anxiolytic-like effects in another model of anxiety, the Vogel conflict test. Male Wistar rats (n=5-9/group) with cannulae aimed at the dorsolateral periaqueductal gray were water deprived for 24 h and pre-exposed to the apparatus where they were allowed to drink for 3 min. After another 24 h-period of water deprivation, they received the microinjections and, 10 min later, were placed into the experimental box. In this box an electrical shock (0.5 mA, 2 s) was delivered in the spout of a drinking bottle at every twenty licks. The animals received a first microinjection of vehicle (0.2 microl) or AM251 (a cannabinoid CB(1) receptor antagonist; 100 pmol) followed, 5 min later, by a second microinjection of vehicle, anandamide (an endocannabinoid, 5 pmol), AM404 (an inhibitor of anandamide uptake, 50 pmol) or URB597 (an inhibitor of Fatty Acid Amide Hydrolase, 0.01 or 0.1 nmol). Anandamide, AM404 and URB597 (0.01 nmol) increased the total number of punished licks. These effects were prevented by AM251. The results give further support to the proposal that facilitation of CB(1) receptor-mediated endocannabinoid neurotransmission in the dorsolateral periaqueductal gray modulates defensive responses.