RESUMO
Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide]; bound with high affinity to the delta opioid receptor (0.2 nM) and with weaker affinity to the mu opioid receptor (72 nM). 5'-O-(3-[(35)S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED(50) = 10.5 micromol/kg or 5 mg/kg) in the mouse hot-plate (48 degrees C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55 degrees C hot-plate test demonstrated the antinociception produced by RWJ-394674 to be sensitive to the nonselective opioid antagonist naloxone as well as to the delta- and mu-selective antagonists, naltrindole and beta-funaltrexamine, respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216 [N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide], which, in contrast to RWJ-394674, had a high affinity for the mu rather than the delta opioid receptor and was an agonist at both. Pharmacokinetic studies in the rat revealed that oral administration of RWJ-394674 rapidly gave rise to detectable plasma levels of RWJ-413216, which reached levels equivalent to those of RWJ-394674 by 1 h. RWJ-413216 itself demonstrated a potent oral antinociceptive effect. Thus, RWJ-394674 is a delta opioid receptor agonist that appears to augment its antinociceptive effect through biotransformation to a novel mu opioid receptor-selective agonist.
Assuntos
Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Administração Oral , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Feminino , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.
Assuntos
Agonistas alfa-Adrenérgicos/síntese química , Analgésicos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Tiofenos/síntese química , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Encéfalo/metabolismo , Eletrocardiografia , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Long-Evans , Ratos Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaAssuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/síntese química , Analgésicos não Narcóticos/síntese química , Imidazóis/síntese química , Tiofenos/síntese química , Administração Oral , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/metabolismo , Analgésicos não Narcóticos/farmacologia , Animais , Ligação Competitiva , Linhagem Celular , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Técnicas In Vitro , Camundongos , Ratos , Receptores Adrenérgicos alfa 2/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacologiaAssuntos
Agonistas alfa-Adrenérgicos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Tiofenos/síntese química , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Ligação Competitiva , Linhagem Celular , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ligantes , Camundongos , Medição da Dor , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 2/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
N-Oxides of centrally acting analgesics generally have minimal analgesic activity. However, the N-oxide of tramadol produced dose-related, long-lasting antinociception in the mouse abdominal irritant, 48 degrees C hot-plate, 55 degrees C hot-plate, and tail-flick tests (ED50 = 15.5, 84.7, 316.4 and 138.2 mg/kg, p.o., respectively). Tramadol N-oxide (T-N-O) (RWJ 38705) was also antinociceptive in the 51 degrees C hot-plate test in male (ED50 = 63.2 mg/kg, i.p.) and female (ED50 = 39.9 mg/kg, i.p.) rats. A characteristic feature of T-N-O was an extended duration of action in these tests (4-5 h). T-N-O had negligible affinity for opioid mu (Ki = 38.5 microM) delta. or kappa receptors (Ki > 100 microM) and, in contrast to tramadol, was essentially devoid of norepinephrine or serotonin neuronal reuptake inhibitory activity (Ki > 100 microM). However, T-N-O displayed tramadol-like characteristics in vivo. There were also significant amounts of tramadol in plasma after T-N-O administration, and the levels resulting from equal oral doses of T-N-O and tramadol were the same, suggesting that the conversion of T-N-O to tramadol was rapid and essentially quantitative. T-N-O was not readily metabolized to tramadol in rat hepatic S9 fraction (< 2%), implying that the conversion might occur in the gastrointestinal tract. Taken together, the results suggest that T-N-O acts as a prodrug for tramadol. T-N-O could offer the clinical benefits of an extended duration of action and a "blunted" plasma concentration spike, possibly leading to an enhanced side-effect profile.
Assuntos
Analgésicos/farmacologia , Tramadol/análogos & derivados , Tramadol/farmacologia , Animais , Transporte Biológico , Relação Dose-Resposta a Droga , Feminino , Fígado/metabolismo , Masculino , Camundongos , Naloxona/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Opioides mu/metabolismo , Tramadol/administração & dosagem , Tramadol/metabolismo , Tramadol/farmacocinéticaRESUMO
In the same mice in which the intracerebroventricular (i.c.v.) administration of antisense oligodeoxyribonucleotide (oligo) directed against the Gi2alpha (but not Gi1alpha, Gi3alpha or G(s)alpha) G-protein subunits attenuated i.c.v. morphine-induced antinociception in the tail-flick test, none of the oligos altered naloxone-precipitated jumping (acute dependence). Likewise, none of the oligos significantly altered morphine-induced constipation. Hence, i.c.v. morphine-induced antinociception might be preferentially mediated via transduction pathway(s) different from constipation or acute dependence, offering novel opportunities for drug discovery.
Assuntos
Analgésicos Opioides/farmacologia , Ventrículos Cerebrais/fisiologia , Constipação Intestinal/fisiopatologia , Proteínas de Ligação ao GTP/genética , Dependência de Morfina/fisiopatologia , Morfina/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Dor , Analgésicos Opioides/administração & dosagem , Animais , Sequência de Bases , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/fisiopatologia , Constipação Intestinal/induzido quimicamente , Injeções Intraventriculares , Cinética , Masculino , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Morfina/administração & dosagem , Naloxona/farmacologia , Oligonucleotídeos Antissenso/administração & dosagem , Tempo de Reação/efeitos dos fármacosRESUMO
The C57BL/6J-bgJ/bgJ (beige-J) mutation imparts a blunted response to intracerebroventricular (i.c.v.) morphine in the tail-flick test, without altered micro-opioid receptor number or morphine affinity. We now report that co-administration of IP3 (36.1 nmol) restored morphine responsiveness of beige-J mice to essentially that of normal littermates (bg+/bg-; ED50 = 3.9 and 3.5 nmol, respectively). IP3 had no effect on morphine-induced antinociception in control animals. Neither myoinositol at 36.1 nmol nor IP6 at the highest testable dose (4.5 nmol) had a similar effect. Myo-inositol at 5.5 mumol restored beige-J responsiveness to that of littermates. These findings implicate some component of the phosphoinositide cycle in the antinociceptive defect of beige-J mice.
Assuntos
Analgésicos/farmacologia , Inositol 1,4,5-Trifosfato/farmacologia , Inositol/farmacologia , Dor/genética , Animais , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Inositol/administração & dosagem , Inositol 1,4,5-Trifosfato/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Dor/psicologia , Medição da Dor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Sistemas do Segundo Mensageiro/fisiologiaRESUMO
Morphine-induced antinociception is antagonized by the K(+)-channel blocker glibenclamide (glyburide; Glib), implicating ATP-sensitive (KATP) K+ channels in the analgesic effect of opioids. The present study examined the generality of this conclusion by measuring the effect of Glib on supraspinal (intracerebroventricular; i.c.v.) antinociception produced by representative mu-opioids and the non-opioids pilocarpine and two alpha 2-adrenoceptor agonists (clonidine and tizanidine) using the mouse tail-flick test. Concurrent administration of Glib (40 micrograms, i.c.v.) produced a significant rightward shift of the dose-response curve of morphine, levorphanol, methadone, pilocarpine, clonidine and tizanidine; a modest, but not statistically significant, rightward shift of the dose-response curves of the mu-selective peptides DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin) and PL017 ([N-Me-Phe3,D-Pro4]-morphiceptin); and no shift of the dose-response curves of alfentanil, carfentanil, fentanyl, sufentanil, or beta-endorphin. Glib produced a leftward shift of the dose-response curve of etorphine. These data support the involvement of KATP-type K+ channels in mediation of supraspinal antinociception, differentiate Glib-sensitive and Glib-insensitive opioid agonists, and reveal fundamental differences among antinociceptive agents in the extent of demonstrable utilization of this transduction pathway.
Assuntos
Analgésicos/farmacologia , Glibureto/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Metadona/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Morfina/farmacologia , Canais de Potássio/efeitos dos fármacosRESUMO
1. The present study examined whether LiCl antagonism of morphine-induced antinociception in mice occurs at mu-opioid receptors. 2. The antinociceptive ED50 value of intracerebroventricular morphine was maximally increased compared to controls 18 hr after LiCl (10 mmol/kg, s.c.) and remained significantly less (P < 0.05) 7 and 14 days after once-daily LiCl treatment. 3. There was no significant difference in [3H]-[D-Ala2,N-MePhe4,Gly- ol5]enkephalin affinity or receptor density compared to controls (KD = 0.43 nM, Bmax = 54.8 +/- 9.3 pM). 4. These results suggest that LiCl's effect is not on mu-opioid receptors, but rather on some distal site.
Assuntos
Encéfalo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Morfina/antagonistas & inibidores , Nociceptores/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Analgésicos/metabolismo , Animais , Encéfalo/fisiologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfina/farmacocinética , Nociceptores/metabolismo , Receptores Opioides mu/efeitos dos fármacosRESUMO
The present study utilized an in vivo antisense strategy to examine the functional interaction of supraspinal mu-opioid receptors with the G protein subunits Gi1 alpha, Gi2 alpha, Gi3 alpha and Gs alpha. Mice were injected intracerebroventricularly (i.c.v.) with 33-base phosphorothioate oligodeoxyribonucleotides (12.5 micrograms) or with vehicle in equal volume (sterile water, 5 microliters) and the antinociceptive responses to i.c.v. morphine [D-Ala2,NMePhe4,Gly5-ol]enkephalin (DAMGO) or sufentanil were determined 18-24 h later using the tail-flick test. Treatment with antisense to Gi2 alpha, but not the other subunits, significantly attenuated morphine-induced antinociception. The degree of attenuation for the three mu-opioid agonists was in the order morphine > DAMGO > sufentanil, the inverse of their intrinsic efficacy.
Assuntos
Analgésicos/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Receptores Opioides mu/metabolismo , Animais , Sequência de Bases , Interações Medicamentosas , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/farmacologia , Proteínas de Ligação ao GTP/genética , Injeções Intraventriculares , Masculino , Camundongos , Dados de Sequência Molecular , Morfina/farmacologia , Oligonucleotídeos Antissenso/administração & dosagem , Receptores Opioides mu/efeitos dos fármacos , Sufentanil/farmacologiaRESUMO
The prevailing view is that supraspinal mu opioid-mediated antinociception in mice is mediated via the mu 1 subtype. The purpose of the present study was to determine if the highly mu-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) antinociception in CXBK mice, which are deficient in brain mu1, but not mu2, opioid receptors. CXBK or normal Crl:CD-1 (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later antinociception was assessed by a standard radiant-heat or 55 degrees C water tail-flick test. Etonitazene produced dose-related antinociception that was blocked by naloxone and by beta-FNA (demonstrating a mu opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of delta opioid receptors). These findings suggest that mu2 opioid receptors are important contributors to opioid-induced supraspinal antinociception in mice.
Assuntos
Benzimidazóis/farmacologia , Ventrículos Cerebrais/fisiologia , Dor/fisiopatologia , Receptores Opioides mu/deficiência , Receptores Opioides mu/fisiologia , Medula Espinal/fisiologia , Animais , Benzimidazóis/administração & dosagem , Ventrículos Cerebrais/efeitos dos fármacos , Relação Dose-Resposta a Droga , Encefalina Leucina/administração & dosagem , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacologia , Temperatura Alta , Injeções Intraventriculares , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Mutantes , Naloxona/administração & dosagem , Naloxona/farmacologia , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medula Espinal/efeitos dos fármacosRESUMO
Scyliorhinin-I amide (SCY-I) (selective for NK-1 and NK-2 receptors) or scyliorhinin-II amide (SCY-II) (selective for NK-3 receptors) were injected either spinally (i.t.; intrathecally) or supraspinally (i.c.v.; intracerebroventricularly) to mice. Following i.c.v. administration, SCI-I and SCY-II produced potent, dose-related reciprocal hindlimb scratching about equipotently (ED50 = 0.05 and 0.08 nmol, respectively). However, following i.t. administration, only SCY-I elicited greater than 50% response (ED50 = 0.07 nmol). Reciprocal hindlimb scratching is a behavioral response that has not been associated previously with neurokinins. These results might provide the first functional in vivo correlate for the differential localization of neurokinin receptor types within the mammalian central nervous system.
Assuntos
Comportamento Animal/efeitos dos fármacos , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-3/metabolismo , Medula Espinal/efeitos dos fármacos , Taquicininas/farmacologia , Sequência de Aminoácidos , Animais , Atropina/farmacologia , Membro Posterior/fisiologia , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Dados de Sequência Molecular , Receptores da Neurocinina-3/efeitos dos fármacos , Taquicininas/administração & dosagemRESUMO
Previous work demonstrated that a single subcutaneous injection of LiCl (10 mmol/kg; 18 h prior) significantly reduces the antinociceptive action of centrally administered (intracerebroventricular; i.c.v.) morphine in the tail-flick and that inositol-1,4,5-trisphosphate (IP3; 20 micrograms) restores the morphine response in LiCl-pretreated mice, implicating a phosphoinositide second messenger pathway in the mediation of morphine-induced analgesia. We now report that LiCl pretreatment shifted the antinociceptive dose-response curve produced by the opioid agonists morphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO) and sufentanil in inverse order of their intrinsic efficacy. These results implicate the phosphoinositide pathway(s) as important determinant(s) of opioid efficacy and are interpreted as evidence for the existence of a second-messenger reserve for opioids of high efficacy and the possible role of the phosphoinositide pathway in the development of morphine tolerance.
Assuntos
Analgésicos/farmacologia , Inositol 1,4,5-Trifosfato/metabolismo , Animais , Cloretos/administração & dosagem , Cloretos/farmacologia , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/farmacologia , Injeções Intraventriculares , Lítio/administração & dosagem , Lítio/farmacologia , Cloreto de Lítio , Masculino , Camundongos , Morfina/farmacologia , Sistemas do Segundo Mensageiro , Sufentanil/farmacologiaRESUMO
The antinociceptive efficacy of [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta 1 agonist) and [D-Ala2,Glu4]deltorphin (delta 2 agonist) was evaluated following intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration in CD-1 and CXBK strains of mice using the radiant heat tail-flick test. Following i.c.v. administration, [D-Ala2,Glu4]deltorphin was effective in CD-1, but not CXBK, mice; DPDPE was approximately equiactive in both strains. While i.c.v. [D-Ala2,Glu4]deltorphin did not produce antinociception in the CXBK mouse, it effectively antagonized the antinociceptive actions of i.c.v. DPDPE. [D-Ala2,Glu4]deltorphin was effective following i.t. administration in both strains. These data suggest possible differences in the supraspinal populations of opioid delta receptor subtypes in the CXBK strain. On the basis of previously established selectivity of these agonists, the CXBK mouse may have a predominate population of supraspinal opioid delta 1, rather than delta 2, receptors.
Assuntos
Analgésicos/farmacologia , Encefalinas/farmacologia , Oligopeptídeos/farmacologia , Receptores Opioides delta/fisiologia , Receptores Opioides mu/fisiologia , Analgésicos/administração & dosagem , Análise de Variância , Animais , D-Penicilina (2,5)-Encefalina , Encefalinas/administração & dosagem , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Oligopeptídeos/administração & dosagem , Medição da Dor , Receptores Opioides delta/efeitos dos fármacosRESUMO
Pretreatment (18 h) of mice with a single s.c. injection of LiCl (10 mmol/kg) reduced the antinociceptive action of centrally administered (i.c.v.) morphine in the tail-flick test (ED50 = 7.7 micrograms) compared to vehicle-treated controls (ED50 = 1.8 micrograms). The coadministration of inositol-1,4,5-trisphosphate (IP3; 20 micrograms) with morphine restored the morphine-induced antinociception (ED50 = 2.4 micrograms) in LiCl-pretreated mice to control levels. These finding implicate a LiCl-sensitive (possibly phosphoinositide) second messenger pathway in the mediation of morphine-induced analgesia.
Assuntos
Analgésicos/farmacologia , Cloretos/farmacologia , Inositol 1,4,5-Trifosfato/farmacologia , Lítio/farmacologia , Morfina/farmacologia , Animais , Cloretos/administração & dosagem , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Lítio/administração & dosagem , Cloreto de Lítio , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacosRESUMO
Intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of morphine to mice antagonized the abdominal constriction induced by an i.p. injection of endothelin-1 (ET-1; 0.1 mg/kg). The ED50 values (95% confidence intervals) were 39.3 (16.5-80.2) ng and 1.5 (0.8-4.9) ng, respectively. The antagonism of ET-1-induced abdominal constriction by morphine was blocked by naloxone (1.0 mg/kg, s.c.) or by 24 h pretreatment with beta-funaltrexamine (beta-FNA; 8.84 micrograms, i.c.v.). These results demonstrate for the first time that the stimulus resulting from an i.p. injection of ET-1 is transmitted via ascending (pain) pathways that are subject to attenuation by opioid (mu) receptor activation. Hence, ET-1-induced abdominal constriction is a new pain model which, given the other pharmacology of ET-1, might represent a unique model with potential specific utility for anginal or other visceral pain.