RESUMO
The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2-64â¯mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (â¼3.5-fold) morphine-conditioned place preference and maraviroc further potentiated these effects (â¼5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24â¯h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids.
Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos/fisiologia , Inflamação/metabolismo , Morfina/farmacologia , Receptores CCR5/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Antagonistas dos Receptores CCR5/farmacologia , Núcleo Caudado/metabolismo , Condicionamento Operante/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Maraviroc/farmacologia , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Recompensa , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genéticaRESUMO
INTRODUCTION: Among novel psychoactive substances notified to EMCDDA and Europol were 1-cyclohexyl-x-methoxybenzene stereoisomers (ortho, meta, and para). These substances share some structural characteristics with phencyclidine and tramadol. Nowadays, no information on the pharmacological and toxicological effects evoked by 1-cyclohexyl-x-methoxybenzene are reported. The aim of this study was to investigate the effect evoked by each one stereoisomer on visual stimulation, body temperature, acute thermal pain, and motor activity in mice. METHODS: Mice were evaluated in behavioral tests carried out in a consecutive manner according to the following time scheme: observation of visual placing response, measures of core body temperature, determination of acute thermal pain, and stimulated motor activity. RESULTS: All three stereoisomers dose-dependent inhibit visual placing response (rank order: meta > ortho > para), induce hyperthermia at lower and hypothermia at higher doses (meta > ortho > para) and cause analgesia to thermal stimuli (para > meta = ortho), while they do not alter motor activity. CONCLUSIONS: For the first time, this study demonstrates that systemic administration of 1-cyclohexyl-x-methoxybenzene compounds markedly inhibit visual response, promote analgesia, and induce core temperature alterations in mice. This data, although obtained in animal model, suggest their possible hazard for human health (i.e., hyperthermia and sensorimotor alterations). In particular, these novel psychoactive substances may have a negative impact in many daily activities, greatly increasing the risk factors for workplace accidents and traffic injuries.
Assuntos
Anisóis/farmacologia , Temperatura Corporal/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Internet , Medição da Dor/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Animais , Anisóis/química , Anisóis/economia , Temperatura Corporal/fisiologia , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/economia , Humanos , Internet/economia , Masculino , Marketing/economia , Camundongos , Medição da Dor/métodos , Estereoisomerismo , Percepção Visual/fisiologiaRESUMO
Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and ß-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.
Assuntos
Constipação Intestinal/tratamento farmacológico , Morfinanos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Polietilenoglicóis/farmacologia , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Constipação Intestinal/induzido quimicamente , Cricetulus , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Fentanila/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Morfinanos/administração & dosagem , Morfina/farmacologia , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Dor/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacosRESUMO
Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance.
Assuntos
Analgésicos Opioides/administração & dosagem , Antineoplásicos/toxicidade , Morfinanos/administração & dosagem , Neuralgia/prevenção & controle , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Animais , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14ß-dihyroxy-4,5α-epoxy-6α-[(3 Ì-isoquinolyl)acetamindo]morphinan (NAQ) <â¯buprenorphine <â¯nalbuphine <â¯morphine =â¯oxycodone <â¯methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (nâ¯=â¯3-4) and schedule-controlled responding (nâ¯=â¯3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32â¯mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.
Assuntos
Analgésicos Opioides/uso terapêutico , Imidazóis/uso terapêutico , Peptídeos Opioides/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides/agonistas , Compostos de Espiro/uso terapêutico , Animais , Macaca mulatta , MasculinoRESUMO
One emerging strategy to address the opioid crisis is the development of mu opioid receptor (MOR) ligands that preferentially signal the G-protein vs. ß-arrestin pathway. The present study compared the relative potency and effectiveness of two G-protein biased (GPB)-MOR ligands TRV130 and SR-14968 to five unbiased MOR ligands (NAQ, nalbuphine, buprenorphine, morphine, and methadone) on therapeutic-related (e.g. antinociception) and abuse-related (e.g. discriminative stimulus effects) endpoints. Male and female rats were tested in a warm water tail-withdrawal procedure (50⯰C) or trained to discriminate fentanyl (0.04â¯mg/kg, SC) from saline in a two-lever food-reinforced discrimination procedure. TRV130 and SR-14968 were approximately two-fold more potent to produce fentanyl stimulus effects vs. antinociception. Morphine, fentanyl, and methadone were significantly more potent in the fentanyl discrimination vs. tail withdrawal procedure. In addition, maximum antinociceptive and discriminative stimulus effects of fixed-proportion fentanyl/naltrexone mixtures (1:0.018, 1:0.054, 1:0.18, 1:0.3, and 1:0.54) were used to quantify 1) the relative in vivo efficacy of the two GPB-MOR agonists and five unbiased MOR ligands, and 2) potential species differences in MOR ligand effects between rats and monkeys. The efficacy-effect function generated from the fentanyl/naltrexone mixtures stratified the five unbiased ligands consistent with agonist-stimulated GTPγS binding (NAQâ¯=â¯nalbuphineâ¯<â¯buprenorphineâ¯<â¯morphineâ¯<â¯methadone). However, TRV130 and SR-14968 produced greater antinociception and less fentanyl-like stimulus effects than was predicted. Furthermore, there was a significant positive correlation between rat and monkey antinociceptive effects. Overall, these results demonstrate GPB-MOR agonists produce undesirable abuse-related effects, albeit with slightly better potency and efficacy ratios compared to unbiased agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.
Assuntos
Aprendizagem por Discriminação/efeitos dos fármacos , Fentanila/farmacologia , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Receptores Opioides mu/agonistas , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Feminino , Masculino , Morfina/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Picralima nitida is used traditionally for management of cough. This study, therefore, investigated the antitussive, expectorant, and analgesic properties of the ethanolic seed extract of Picralima nitida (PNE), and ascertained its safety for use. Presence of secondary metabolites, and safety of PNE (10-2000 mg/kg) were evaluated by preliminary phytochemical screening, and by Irwin's test respectively. Percentage reduction in cough count, percentage increase in latency of cough, and percentage protection offered by PNE were established by the citric acid-induced cough, acetylcholine- and Histamine-induced bronchoconstriction models. Dunkin-Hartley guinea pigs were treated with 100-500 mg/kg PNE or reference drugs, dihydrocodiene, atropine, mepyramine. Expectorant property of PNE (100-1000 mg/kg) was determined using the tracheal phenol red secretion; with ammonium chloride as a reference medication. Percentage maximal possible analgesic effect in the tail immersion test and the total nociceptive score in acetic acid-induced abdominal writhes, after treatment of BALB/c mice with PNE (100-500 mg/kg), diclofenac, and morphine were also estimated. Phytochemical screening revealed the presence of tannins, alkaloids, glycosides, saponins, steroids, terpenoids and anthraquinones. PNEdid not cause any extract-related physical, pharmacological and CNS toxicities or mortality; sedation was observed at doses 1000-2000 mg/kg. It showed significant dose-dependent reduction in cough count, and increased cough latency. PNE (1000 mg/kg) enhanced tracheal phenol red secretion. PNE (100-500 mg/kg) significantly and dose dependently increased tail withdrawal latencies, and nociceptive score. PNE has antitussive, expectorant, and analgesic properties, with an LD50>2000 mg/kg.
RESUMO
The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein and ß-arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G-protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP-ß-arrestin 2 interactions and displayed reduced potency at mu/ß-arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long-lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB-612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.
RESUMO
GHRP-2 is a synthetic agonist of ghrelin receptor. GHRP-2 has similar physiological functions with ghrelin. In our previous study, ghrelin (i.c.v.) could induce analgesic effect through an interaction with GHS-R1α and with the central opioid system in the acute pain in mice. To date, the function of GHRP-2 in pain processing was not understood. Therefore the aim of this study was to investigate the effects of GHRP-2 on pain modulation at supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of GHRP-2 (0.1, 0.3, 1, 3 and 10 nmol/L) produced a concentration- and time-related antinociceptive effect. This effect could be fully antagonized by GHS-R1α antagonist [d-Lys(3)]-GHRP-6, indicating that the analgesic effect induced by GHRP-2 is mediated through the activation of GHS-R1α. Interestingly, naloxone, naltrindole and nor-binaltorphimine, but not ß-funaltrexamine, could also block the analgesic effect markedly, suggesting that δ- and κ-opioid receptor is involved in the analgesic response evoked by GHRP-2. Moreover, i.c.v. administration of GHRP-2 potentiated the analgesic effect induced by morphine (i.c.v., 1 nmol/L) and this potentiated effect could not be reversed by [d-Lys(3)]-GHRP-6. Thus these findings may be a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation. Furthermore, GHRP-2 may be a promising peptide for developing new analgesic drugs.
Assuntos
Analgésicos/administração & dosagem , Oligopeptídeos/administração & dosagem , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Analgésicos Opioides/administração & dosagem , Animais , Injeções Intraventriculares , Masculino , Camundongos , Morfina/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Oligopeptídeos/farmacologia , Percepção da Dor/efeitos dos fármacos , Receptores de Grelina/antagonistas & inibidoresRESUMO
Ghrelin, an acylated 28-amino peptide secreted in the gastric endocrine cells, has been demonstrated to stimulate the release of growth hormone, increase food intake, and inhibit pro-inflammatory cascade, etc. Ghrelin mainly combines with its receptor (GHS-R1α) to play the role in physiological and pathological functions. It has been reported that ghrelin plays important roles in the control of pain through interaction with the opioid system in inflammatory pain and acute pain. However, very few studies show the effect of supraspinal ghrelin system on antinociception induced by intraperitoneal (i.p.) administration of morphine. In the present study, intracerebroventricular (i.c.v.) injection of ghrelin (0.1, 1, 10 and 100 nmol/L) produced inhibition of systemic morphine (6 mg/kg, i.p.) analgesia in the tail withdrawal test. Similarly, i.c.v. injection GHRP-6 and GHRP-2 which are the agonists of GHS-R1α, also decreased analgesia effect induced by morphine injected intraperitoneally in mice. Furthermore, these anti-opioid activities of ghrelin and related peptides were not blocked by pretreatment with the GHS-R1α selective antagonist [d-Lys(3)]-GHRP-6 (100 nmol/L, i.c.v.). These results demonstrated that central ghrelin and related peptides could inhibit the analgesia effect induced by intraperitoneal (i.p.) administration of morphine. The anti-opioid effects of ghrelin and related peptides do not interact with GHS-R1a. These findings may pave the way for a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation.