RESUMO
Cancer pain is an important clinical problem and may not respond satisfactorily to the current analgesic therapy. We have characterized a novel and potent analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in a rat model of cancer pain induced by intraplantar injection of Walker 256 carcinoma cells. Intraplantar injection of tumor cells caused the development of hyperalgesia and allodynia, detected on day 5 after tumor cell inoculation. Crotalphine (6 µg/kg), administered p.o., blocked both phenomena. The antinociceptive effect was detected 1 h after treatment and lasted for up to 48 h. Intraplantar injection of nor-binaltorphimine (50 g/paw), a selective antagonist of κ-opioid receptors, antagonized the antinociceptive effect of the peptide, whereas N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864, 10 µg/paw), a selective antagonist of δ-opioid receptors, partially reversed this effect. On the other hand, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP, 20 g/paw), an antagonist of µ-opioid receptors, did not modify crotalphine-induced antinociception. These data indicate that crotalphine induces a potent and long lasting opioid-mediated antinociception in cancer pain.
Assuntos
Analgésicos/farmacologia , Modelos Animais de Doenças , Neoplasias/complicações , Dor/tratamento farmacológico , Peptídeos/farmacologia , Receptores Opioides delta/fisiologia , Receptores Opioides kappa/fisiologia , Administração Oral , Analgésicos/administração & dosagem , Animais , Linhagem Celular Tumoral , Dor/etiologia , Peptídeos/administração & dosagem , RatosRESUMO
BACKGROUND/AIMS: In this study we analyzed the mechanisms underlying celecoxib-induced analgesia in a model of inflammatory pain in rats, using the intracerebroventricular (i.c.v.) administration of selective opioid and cannabinoid antagonists. METHODS AND RESULTS: Analgesic effects of celecoxib were prevented by selective µ-(ß-funaltrexamine) and δ-(naltrindole), but not κ-(nor-binaltorphimine) opioid antagonists, given i.c.v. 30 min before celecoxib. Similar pretreatment with AM 251, but not SR 144528, cannabinoid CB(1) and CB(2) receptor antagonists, respectively, prevented celecoxib-induced analgesia. The fatty acid amide hydrolase inhibitor, URB 597, also prevented celecoxib-induced analgesia. CONCLUSIONS: Our data provided further evidence for the involvement of endogenous opioids and revealed a new cannabinoid component of the mechanism(s) underlying celecoxib-induced analgesia.
Assuntos
Analgésicos/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Receptores Opioides delta/fisiologia , Receptores Opioides mu/fisiologia , Sulfonamidas/farmacologia , Animais , Carragenina , Celecoxib , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidoresRESUMO
Crotalphine, a 14 amino acid peptide first isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces a peripheral long-lasting and opioid receptor-mediated antinociceptive effect in a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. In the present study, we further characterized the molecular mechanisms involved in this effect, determining the type of opioid receptor responsible for this effect and the involvement of the nitric oxide-cyclic GMP pathway and of K⺠channels. Crotalphine (0.2 or 5 µg/kg, orally; 0.0006 µg/paw), administered on day 14 after nerve constriction, inhibited mechanical hyperalgesia and low-threshold mechanical allodynia. The effect of the peptide was antagonized by intraplantar administration of naltrindole, an antagonist of δ-opioid receptors, and partially reversed by norbinaltorphimine, an antagonist of κ-opioid receptors. The effect of crotalphine was also blocked by 7-nitroindazole, an inhibitor of the neuronal nitric oxide synthase; by 1H-(1,2,4) oxadiazolo[4,3-a]quinoxaline-1-one, an inhibitor of guanylate cyclase activation; and by glibenclamide, an ATP-sensitive K⺠channel blocker. The results suggest that peripheral δ-opioid and κ-opioid receptors, the nitric oxide-cyclic GMP pathway, and ATP-sensitive K⺠channels are involved in the antinociceptive effect of crotalphine. The present data point to the therapeutic potential of this peptide for the treatment of chronic neuropathic pain.
Assuntos
Analgésicos/farmacologia , Arginina/fisiologia , GMP Cíclico/fisiologia , Canais KATP/fisiologia , Neuralgia/tratamento farmacológico , Óxido Nítrico/fisiologia , Peptídeos/farmacologia , Animais , Masculino , Ratos , Ratos Wistar , Receptores Opioides delta/fisiologia , Receptores Opioides kappa/fisiologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND AND PURPOSE: It has been demonstrated that cannabinoids evoke the release of endogenous opioids to produce antinociception; however, no information exists regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids are involved in central antinociception induced by activation of mu-, delta- and kappa-opioid receptors. EXPERIMENTAL APPROACH: Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. Morphine (5 microg), SNC80 (4 microg), bremazocine (4 microg), AM251 (2 and 4 microg), AM630 (2 and 4 microg) and MAFP (0.1 and 0.4 microg) were administered by the intracerebroventricular route. KEY RESULTS: The CB(1)-selective cannabinoid receptor antagonist AM251 completely reversed the central antinociception induced by morphine in a dose-dependent manner. In contrast, the CB(2)-selective cannabinoid receptor antagonist AM630 did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor, MAFP, significantly enhanced the antinociception induced by morphine. In contrast, the antinociceptive effects of delta- and kappa-opioid receptor agonists were not affected by the cannabinoid antagonists. The antagonists alone caused no hyperalgesic or antinociceptive effects. CONCLUSIONS AND IMPLICATIONS: The results provide evidence for the involvement of cannabinoid CB(1) receptors in the central antinociception induced by activation of mu-opioid receptors by the agonist morphine. The release of endocannabinoids appears not to be involved in central antinociception induced by activation of kappa- and delta-opioid receptors.
Assuntos
Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Receptores Opioides delta/fisiologia , Receptores Opioides kappa/fisiologia , Receptores Opioides mu/fisiologia , Analgésicos Opioides/farmacologia , Animais , Indóis/farmacologia , Masculino , Camundongos , Medição da Dor/métodos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistasRESUMO
To enhance analgesia, combination of analgesics drugs of proven efficacy is a strategy which is accompanied by a reduction of adverse effects. The present study was undertaken to characterize the antinociceptive interaction of morphine with different non-steroidal anti-inflammatory drugs (NSAIDs) using isobolographic analysis and the writhing test of mice. One of the possible mechanisms of action of spinally administered morphine with non-steroidal antiinflammatory drugs was investigated using the DOR antagonist naltrindole. The study demonstrated a synergistic antinociception of spinal administered combinations of morphine with the following NSAIDs agents: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supraadditive effect seems to be independent of the selectivity of each NSAIDs to inhibit COX-1 or COX-2. The findings of the present work suggest that the combinations of opioids and non-steroidal anti-inflammatory drugs have a direct action on spinal processing of the nociceptive information, which may achieved by additional mechanisms independent of prostaglandin synthesis inhibition and/or activation of opioid receptors. The lack of effect of naltrindole to modify the analgesic activity of the combination of opioids and NSAIDs indicates that others pain regulatory systems are involved in this central action. Therefore, these combinations could be a viable alternative to clinical pain management, especially trough multimodal analgesia.
Assuntos
Analgésicos Opioides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Morfina/farmacologia , Naltrexona/análogos & derivados , Receptores Opioides delta/fisiologia , Medula Espinal/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Animais , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/uso terapêutico , Sinergismo Farmacológico , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos , Morfina/administração & dosagem , Morfina/uso terapêutico , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Dor/tratamento farmacológico , Dor/fisiopatologia , Receptores Opioides delta/antagonistas & inibidores , Medula Espinal/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: Periodontal disease is a chronic inflammatory condition of the tooth supporting tissues, the periodontium. Opioids have been shown to account for the relief of various chronic and acute inflammatory conditions. The aim of the present study was to investigate the participation of peripheral opioid receptors in development of periodontal disease. MATERIAL AND METHODS: Morphine and selective agonists and antagonists of opioid receptors were used in an experimental model of ligature-induced periodontal disease in rats. To evaluate the development of disease, the loss of fiber attachment, alveolar bone and number of cells in periodontal tissues were assessed. Measurements of these indicators were obtained by morphometric analysis of histological sections of periodontal-diseased tissues stained with hematoxylin and eosin. RESULTS: Local administration of either morphine or a selective kappa-opioid agonist for three consecutive days from the onset of periodontal disease reduced the loss of periodontal tissues, without changing the number of leukocytes in inflamed periodontium. Nor-binaltorphimine, a selective kappa-antagonist, reversed the beneficial effects of both morphine and the compound U-50,488 in this model. The use of either an agonist or an antagonist of delta-opioid receptors, however, did not affect disease progression. CONCLUSION: Our results showed that the beneficial effect of opioids in periodontal disease depended mainly on the activation of specific kappa-opioid receptors located in the periphery. Activation of such receptors could be considered in the management of periodontal disease, since it would not present the classical central side-effects associated with opioid use.
Assuntos
Periodontite Crônica/tratamento farmacológico , Periodontite Crônica/fisiopatologia , Receptores Opioides kappa/fisiologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Morfina/farmacologia , Morfina/uso terapêutico , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Sistema Nervoso Periférico/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/fisiologia , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidoresRESUMO
Previous work has shown that nitric oxide (NO) mediates the antinociceptive effect of Crotalus durissus terrificus venom on carrageenin-induced hyperalgesia. In the present study the role of constitutive neuronal or of inducible form of nitric oxide synthase on venom effect was determined. The rat paw prostaglandin E(2) (PGE(2))-induced mechanical hyperalgesia model was used for nociceptive evaluation. The venom (200 microg/kg) administered per oz immediately before prostaglandin induced antinociception that persisted for 120 h. The characterisation of the antinociceptive effect of the venom in this model of hyperalgesia showed that kappa and delta-opioid receptors are involved in this effect. 7-nitroindazole (7-NI), a neuronal nitric oxide synthase (NOS) inhibitor, but not L-N(6)-(1-iminoethyl)lysine (L-NIL), an inhibitor of the inducible form of NOS, injected by intraplantar (i.pl.) route, antagonized the antinociceptive effect of the venom. The i.pl. administration of 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective guanylate cyclase inhibitor, blocked antinociception, whereas Rp-cGMP triethylamine, a cGMP-dependent protein kinase inhibitor, partially reversed this effect. These data indicate that peripheral kappa- and delta-opioid receptors are involved in the antinociceptive effect of Crotalus durissus terrificus on prostaglandin E(2)-induced hyperalgesia. Peripheral nitric oxide, generated by neuronal NO synthase, and cGMP/PKc are responsible, at least partially, for the molecular mechanisms of venom effect.
Assuntos
Analgésicos/farmacologia , Venenos de Crotalídeos/farmacologia , Crotalus , Óxido Nítrico Sintase/metabolismo , Receptores Opioides delta/fisiologia , Receptores Opioides kappa/fisiologia , Animais , Dinoprostona/farmacologia , Antagonismo de Drogas , Inibidores Enzimáticos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Indazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistasRESUMO
Repeated amphetamine administration results in behavioral sensitization, an enduring behavioral transformation expressed after short and long periods of withdrawal. To investigate the participation of the opioid system in amphetamine-induced behavioral sensitization, we studied the effect of naloxone, an opioid receptor antagonist, on the expression of behavioral sensitization tested after short- (2 days) and long-term (14 days) withdrawal periods. In addition, using quantitative competitive RT-PCR, we examined the levels of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) mRNA in the nucleus accumbens shell (NAcSh) and ventral tegmental area (VTA) of behaviorally sensitized rats, at these two withdrawal times. This study showed that whereas naloxone did not modify the expression of behavioral sensitization tested after 2 days of withdrawal, it completely blocked the expression when tested after 14 days of withdrawal. DOR and MOR mRNA levels were not modified in the NAcSh of rats expressing behavioral sensitization after 2 or 14 days of withdrawal. Conversely, DOR and MOR mRNA levels were elevated in the VTA of animals expressing behavioral sensitization after 2 days of withdrawal. However, whereas DOR mRNA returned to control levels, MOR mRNA levels remained elevated in animals expressing behavioral sensitization after 14 days of withdrawal. These results indicate a striking difference between the role played by opioid receptors in the expression of amphetamine-induced behavioral sensitization, when tested after short- or long-term withdrawal periods. In addition, our results support the notion that repeated amphetamine-induced changes in opioid receptor expression may contribute to the perpetuation of psychostimulant abuse and/or relapse.
Assuntos
Anfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores Opioides delta/fisiologia , Receptores Opioides mu/fisiologia , Síndrome de Abstinência a Substâncias/metabolismo , Anfetamina/efeitos adversos , Animais , Masculino , Atividade Motora/fisiologia , Núcleo Accumbens/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/biossíntese , Receptores Opioides mu/biossíntese , Área Tegmentar Ventral/metabolismoRESUMO
The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of inflammatory hyperalgesia induced by carrageenin. The rat paw pressure test was applied before and 3 h after the intraplantar (i.pl.) injection of carrageenin. The venom administered per os before and 1 or 2 h after carrageenin blocked hyperalgesia. When carrageenin was injected in both hind paws and naloxone into one hind paw, antinociception was abolished only in the paw injected with naloxone. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) and nor-binaltorphimine, antagonists of micro- and kappa-opioid receptors, respectively, did not alter the effect of the venom. N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI 174,864), an antagonist of delta-opioid receptors, antagonised this effect. Prolonged administration of the venom did not induce tolerance to this antinociceptive effect. N(G)-methyl-L-arginine (L-NMMA) and methylene blue, inhibitors of nitric oxide synthase and soluble guanylate cyclase, respectively, injected i.pl., antagonised antinociception. These data indicate that both delta-opioid receptors and nitric oxide participate in the mediation of the peripheral antinociceptive effect of C. durissus terrificus venom.
Assuntos
Analgésicos não Narcóticos/farmacologia , Venenos de Crotalídeos/farmacologia , Óxido Nítrico/fisiologia , Receptores Opioides delta/fisiologia , Animais , Arginina/metabolismo , Carragenina , GMP Cíclico/metabolismo , Edema/induzido quimicamente , Edema/prevenção & controle , Inibidores Enzimáticos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Masculino , Azul de Metileno/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , ômega-N-Metilarginina/farmacologiaRESUMO
Endogenous enkephalins and delta opiates affect sensory function and pain sensation by inhibiting synaptic transmission in sensory circuits via delta opioid receptors (DORs). DORs have long been suspected of mediating these effects by modulating voltage-dependent Ca(2+) entry in primary sensory neurons. However, not only has this hypothesis never been validated in these cells, but in fact several previous studies have only turned up negative results. By using whole-cell current recordings, we show that the delta enkephalin analog [D-Ala(2), D-Leu(5)]-enkephalin (DADLE) inhibits, via DORs, L-, N-, P-, and Q-high voltage-activated Ca(2+) channel currents in cultured rat dorsal root ganglion (DRG) neurons. The percentage of responding cells was remarkably high (75%) within a novel subpopulation of substance P-containing neurons compared with the other cells (18-35%). DADLE (1 microM) inhibited 32% of the total barium current through calcium channels (I(Ba)). A delta (naltrindole, 1 microM), but not a mu (beta-funaltrexamine, 5 microM), antagonist prevented the DADLE response, whereas a DOR-2 subtype (deltorphin-II, 100 nM), but not a DOR-1 (DPDPE, 1 microM), agonist mimicked the response. L-, N-, P-, and Q-type currents contributed, on average, 18, 48, 14, and 16% to the total I(Ba) and 19, 50, 26, and 20% to the DADLE-sensitive current, respectively. The drug-insensitive R-type current component was not affected by the agonist. This work represents the first demonstration that DORs modulate Ca(2+) entry in sensory neurons and suggests that delta opioids could affect diverse Ca(2+)-dependent processes linked to Ca(2+) influx through different high-voltage-activated channel types.