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1.
Molecules ; 26(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684749

RESUMO

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.


Assuntos
Dor Crônica/tratamento farmacológico , Receptores de Angiotensina/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Humanos , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Manejo da Dor/métodos , Receptores de Angiotensina/metabolismo , Receptores Opioides/agonistas , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
2.
Life Sci ; 285: 119996, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34597607

RESUMO

AIMS: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting µ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. MAIN METHODS: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. KEY FINDINGS: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. SIGNIFICANCE: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.


Assuntos
Analgésicos Opioides/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dor Nociceptiva/tratamento farmacológico , Pentazocina/farmacologia , Receptores Opioides mu/agonistas , Tapentadol/farmacologia , Tetra-Hidronaftalenos/farmacologia , Inibidores da Captação Adrenérgica/química , Inibidores da Captação Adrenérgica/farmacologia , Analgésicos Opioides/química , Analgésicos Opioides/uso terapêutico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Agonismo de Drogas , Antagonismo de Drogas , Células HEK293 , Humanos , Camundongos , Pentazocina/química , Pentazocina/uso terapêutico , Receptores Adrenérgicos/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Tapentadol/química , Tapentadol/uso terapêutico , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/uso terapêutico
3.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361663

RESUMO

Opioid-associated overdoses and deaths due to respiratory depression are a major public health problem in the US and other Western countries. In the past decade, much research effort has been directed towards the development of G-protein-biased µ-opioid receptor (MOP) agonists as a possible means to circumvent this problem. The bias hypothesis proposes that G-protein signaling mediates analgesia, whereas ß-arrestin signaling mediates respiratory depression. SR-17018 was initially reported as a highly biased µ-opioid with an extremely wide therapeutic window. It was later shown that SR-17018 can also reverse morphine tolerance and prevent withdrawal via a hitherto unknown mechanism of action. Here, we examined the temporal dynamics of SR-17018-induced MOP phosphorylation and dephosphorylation. Exposure of MOP to saturating concentrations of SR-17018 for extended periods of time stimulated a MOP phosphorylation pattern that was indistinguishable from that induced by the full agonist DAMGO. Unlike DAMGO-induced MOP phosphorylation, which is reversible within minutes after agonist washout, SR-17018-induced MOP phosphorylation persisted for hours under otherwise identical conditions. Such delayed MOP dephosphorylation kinetics were also found for the partial agonist buprenorphine. However, buprenorphine, SR-17018-induced MOP phosphorylation was fully reversible when naloxone was included in the washout solution. SR-17018 exhibits a qualitative and temporal MOP phosphorylation profile that is strikingly different from any other known biased, partial, or full MOP agonist. We conclude that detailed analysis of receptor phosphorylation may provide novel insights into previously unappreciated pharmacological properties of newly synthesized MOP ligands.


Assuntos
Analgésicos Opioides/farmacologia , Buprenorfina/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Analgésicos Opioides/química , Buprenorfina/química , Tolerância a Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/química , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Overdose de Opiáceos/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transfecção , beta-Arrestina 2/metabolismo
4.
Anesthesiology ; 135(3): 482-493, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237134

RESUMO

BACKGROUND: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and µ receptors produces analgesia with reduced side effects in nonhuman primates. METHODS: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with µ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. RESULTS: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] µg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] µg/kg). Pretreatment with antagonists selective for nociceptin and µ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 µg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 µg; 3,009 ± 1,474 scratches). CONCLUSIONS: In nonhuman primates, the µ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/µ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.


Assuntos
Indóis/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptores Opioides/agonistas , Compostos de Espiro/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Fentanila/administração & dosagem , Injeções Espinhais , Macaca mulatta , Masculino , Peptídeos Opioides/administração & dosagem , Receptores Opioides/fisiologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/fisiologia
5.
J Med Chem ; 64(14): 10139-10154, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34236190

RESUMO

A new series of propionamide derivatives was developed as dual µ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.


Assuntos
Amidas/farmacologia , Analgésicos Opioides/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/química , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 223: 113658, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175542

RESUMO

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ1R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the µ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB1R). Overwhelming pharmacological and genetic evidence indicates that σ1R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ1Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ1R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ1R antagonism represents a promising avenue for the development of potent and safer analgesics.


Assuntos
Analgésicos Opioides/química , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/agonistas , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Benzopiranos/química , Benzopiranos/metabolismo , Humanos , Ligantes , Dor/tratamento farmacológico , Piperazinas/química , Piperazinas/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo
7.
Mol Pharmacol ; 100(3): 217-223, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34135098

RESUMO

Regulators of G protein signaling (RGS) proteins modulate signaling by G protein-coupled receptors. Using a knock-in transgenic mouse model with a mutation in Gαo that does not bind RGS proteins (RGS-insensitive), we determined the effect of RGS proteins on presynaptic µ opioid receptor (MOR)-mediated inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG). The MOR agonists [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and met-enkephalin (ME) inhibited evoked inhibitory postsynaptic currents (eIPSCs) in the RGS-insensitive mice compared with wild-type (WT) littermates, respectively. Fentanyl inhibited eIPSCs similarly in both WT and RGS-insensitive mice. There were no differences in opioid agonist inhibition of spontaneous GABA release between the genotypes. To further probe the mechanism underlying these differences between opioid inhibition of evoked and spontaneous GABA release, specific myristoylated Gα peptide inhibitors for Gαo1 and Gαi1-3 that block receptor-G protein interactions were used to test the preference of agonists for MOR-Gα complexes. The Gαo1 inhibitor reduced DAMGO inhibition of eIPSCs, but Gαi1-3 inhibitors had no effect. Both Gαo1 and Gαi1-3 inhibitors separately reduced fentanyl inhibition of eIPSCs but had no effects on ME inhibition. Gαi1-3 inhibitors blocked the inhibitory effects of ME and fentanyl on miniature postsynaptic current (mIPSC) frequency, but both Gαo1 and Gαi1-3 inhibitors were needed to block the effects of DAMGO. Finally, baclofen-mediated inhibition of GABA release is unaffected in the RGS-insensitive mice and in the presence of Gαo1 and Gαi1-3 inhibitor peptides, suggesting that GABAB receptor coupling to G proteins in vlPAG presynaptic terminals is different than MOR coupling. SIGNIFICANCE STATEMENT: Presynaptic µ opioid receptors (MORs) in the ventrolateral periaqueductal gray are critical for opioid analgesia and are negatively regulated by RGS proteins. These data in RGS-insensitive mice provide evidence that MOR agonists differ in preference for Gαo versus Gαi and regulation by RGS proteins in presynaptic terminals, providing a mechanism for functional selectivity between agonists. The results further define important differences in MOR and GABAB receptor coupling to G proteins that could be exploited for new pain therapies.


Assuntos
Subunidade alfa Gi2 de Proteína de Ligação ao GTP/fisiologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Terminações Pré-Sinápticas/fisiologia , Receptores Opioides mu/fisiologia , Ácido gama-Aminobutírico/metabolismo , Analgésicos Opioides/farmacologia , Animais , Baclofeno/farmacologia , Feminino , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Proteínas RGS/metabolismo , Receptores de GABA-B/metabolismo , Receptores Opioides mu/agonistas
8.
Nat Commun ; 12(1): 3858, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158473

RESUMO

Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.


Assuntos
Mitragyna/química , Extratos Vegetais/farmacologia , Receptores Opioides mu/agonistas , Alcaloides de Triptamina e Secologanina/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Etilenoglicol/química , Humanos , Camundongos Knockout , Modelos Químicos , Estrutura Molecular , Extratos Vegetais/química , Ligação Proteica , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Alcaloides de Triptamina e Secologanina/química
9.
J Med Chem ; 64(11): 7778-7808, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34011153

RESUMO

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains µ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.


Assuntos
Antagonistas de Dopamina/química , Ligantes , Receptores de Dopamina D3/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/uso terapêutico , Modelos Animais de Doenças , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/uso terapêutico , Desenho de Fármacos , Transferência Ressonante de Energia de Fluorescência , Camundongos , Simulação de Acoplamento Molecular , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Dor/tratamento farmacológico , Manejo da Dor , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Receptores Opioides mu/agonistas , Relação Estrutura-Atividade
10.
J Med Chem ; 64(10): 6656-6669, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33998786

RESUMO

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.


Assuntos
Peptídeos/química , Receptores Opioides mu/agonistas , Receptores Opioides/agonistas , Animais , Sítios de Ligação , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Modelos Animais de Doenças , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Simulação de Dinâmica Molecular , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Receptores Opioides/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade
11.
Am J Drug Alcohol Abuse ; 47(4): 455-466, 2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-33909525

RESUMO

Background: Originally believed to be an atypical antidepressant acting at serotonin transporters, tianeptine is now known to also be an atypical agonist at mu-opioid receptors. Its nonmedical use may be increasing amidst the broader context of novel drug and supplement use.Objectives: To analyze social-media text from current, former, and prospective tianeptine users for better understanding of their conceptualizations of tianeptine, motives for and patterns of use, and reported benefits and harms.Methods: Reddit posts were obtained and thematically coded; additional quantitative analyses were conducted.Results: A total of 210 posts mentioning tianeptine were made between 2012 and 2020. Eighteen thematic categories were identified, 10 of which were consistent with expected themes. Two independent raters coded all text, generating 1,382 unique codes, of which 1,090 were concordant (78.9% interrater agreement). Tianeptine use was frequently associated with use of other drugs, particularly kratom, phenibut, and racetams. People conceptualized and variously used tianeptine as an opioid, antidepressant, and "nootropic" (cognitive enhancer). Between 2014 and 2020, mentions of positive effects decreased, while mentions of adverse effects and withdrawal increased. Motivations for use included substitution or withdrawal mitigation for other drugs (especially opioids) and for kratom itself; self-treatment for psychiatric symptoms; and improvement of quality of life, mood, or performance. Descriptions of tolerance, withdrawal, and addiction were evident. Intravenous use was rare and strongly discouraged, with detrimental effects described.Conclusion: Tianeptine is recognized as an opioid (though not only an opioid) in online communities. Posts describe benefits, acute risks, and patterns of co-use that warrant greater clinical attention.


Assuntos
Usuários de Drogas/psicologia , Mídias Sociais , Tiazepinas/administração & dosagem , Humanos , Receptores Opioides mu/agonistas
12.
Eur J Pharmacol ; 899: 174007, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705801

RESUMO

G-protein-biased agonists with reduced ß-arrestin-2 activation are being investigated as safer alternatives to clinically-used opioids. ß-arrestin-2 has been implicated in the mechanism of opioid-induced antinociceptive tolerance. Opioid-induced analgesic tolerance is classically considered as centrally-mediated, but recent reports implicate nociceptive dorsal root ganglia neurons as critical mediators in this process. Here, we investigated the role of ß-arrestin-2 in the mechanism of opioid tolerance in dorsal root ganglia nociceptive neurons using ß-arrestin-2 knockout mice and the G-protein-biased µ-opioid receptor agonist, TRV130. Whole-cell current-clamp electrophysiology experiments revealed that 15-18-h overnight exposure to 10 µM morphine in vitro induced acute tolerance in ß-arrestin-2 wild-type but not knockout neurons. Furthermore, in wild-type neurons circumventing ß-arrestin-2 activation by overnight treatment with 200 nM TRV130 attenuated tolerance. Similarly, acute morphine tolerance in vivo in ß-arrestin-2 knockout mice was prevented in the warm-water tail-withdrawal assay. Treatment with 30 mg/kg TRV130 s.c. also inhibited acute antinociceptive tolerance in vivo in wild-type mice. Alternately, in ß-arrestin-2 knockout neurons tolerance induced by 7-day in vivo exposure to 50 mg morphine pellet was conserved. Likewise, ß-arrestin-2 deletion did not mitigate in vivo antinociceptive tolerance induced by 7-day exposure to 25 mg or 50 mg morphine pellet in both female or male mice, respectively. Consequently, these results indicated that ß-arrestin-2 mediates acute but not chronic opioid tolerance in dorsal root ganglia neurons and to antinociception in vivo. This suggests that opioid-induced antinociceptive tolerance may develop even in the absence of ß-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Gânglios Espinais/efeitos dos fármacos , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Receptores Opioides mu/agonistas , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , beta-Arrestina 2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Masculino , Camundongos Knockout , Neurônios/metabolismo , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Fatores de Tempo , beta-Arrestina 2/deficiência , beta-Arrestina 2/genética
13.
Biol Pharm Bull ; 44(2): 159-161, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518669

RESUMO

The agonistic activity of fluorinated and nonfluorinated fentanyl analogs on µ-opioid receptor was investigated using a cell-based assay system. Based on the activity, fentanyl analogs were ranked as follows: fentanyl > isobutyrylfentanyl ≈ butyrylfentanyl ≈ methoxyacetylfentanyl > acetylfentanyl. However, among the fentanyl analogs fluorinated on the N-phenyl ring, 2-fluoro analogs and 3-fluoro analogs showed the strongest and weakest activities, respectively. These results suggest that the 2-fluorinated isomers of fentanyl analogs are more likely to cause poisoning.


Assuntos
Analgésicos Opioides/farmacologia , Fentanila/farmacologia , Receptores Opioides mu/agonistas , Animais , Células CHO , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Fentanila/análogos & derivados
14.
Psychopharmacology (Berl) ; 238(6): 1585-1592, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33585961

RESUMO

RATIONALE: Opioid and GABAA receptors are both located in central nociceptive pathways, and compounds that activate these receptors have pain-relieving properties. To date, the interactive effects of concurrent administration of these compounds in preclinical models of pain-like behaviors have not been assessed. OBJECTIVE: The purpose of this study was to examine the interactive effects of the µ-opioid agonist morphine and the α2GABAA and α3GABAA receptor positive allosteric modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024) in preclinical models of mechanical hyperalgesia and thermal nociception. METHODS: The antihyperalgesic and antinociceptive effects of morphine and MP-III-024 administered alone were assessed initially, followed by fixed-ratio mixtures of MP-III-024/morphine combinations. Drug interaction data were analyzed using isobolographic and dose-addition analyses. All studies were conducted in male CD-1 mice. RESULTS: In the assay of mechanical hyperalgesia, each compound produced dose-dependent antihyperalgesic effects, whereas only morphine was effective on thermal nociception. Fixed-ratio mixtures of MP-III-024/morphine were also dose-dependently effective in both procedures. These drug combination studies revealed that morphine and MP-III-024 produced supra-additive (synergistic) effects in both assays, depending on their relative proportions. CONCLUSIONS: These results demonstrate an interaction between α2GABAA and α3GABAA receptor- and µ-opioid receptor-mediated signals and suggest that combination therapy may be useful for the treatment of pain-related disorders.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Dor/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Sinergismo Farmacológico , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Receptores de GABA-A/efeitos dos fármacos , Receptores Opioides mu/agonistas
15.
Eur J Pharmacol ; 898: 173979, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33639195

RESUMO

The use of morphine is controversial due to the incidence of rewarding behavior, respiratory depression, and tolerance, leading to increased drug dose requirements, advancing to morphine addiction. To overcome these barriers, strategies have been taken to combine morphine with other analgesics. Neuropeptide B23 and neuropeptide W23 (NPB23 and NPW23) are commonly used to relieve inflammatory pain and neuropathic pain. As NPB23 and NPW23 system shares similar anatomical basis with opioid system at least in the spinal cord we hypothesized that NPB23 or NPW23 and morphine may synergistically relieve inflammatory pain and neuropathic pain. To test this hypothesis, we demonstrated that µ opioid receptor and NPBW1 receptor (receptor of NPB23 and NPW23) are colocalized in the superficial dorsal horn of the spinal cord. Secondly, co-administration of morphine witheitherNPB23 or NPW23 synergistically attenuated inflammatory and neuropathic pain. Furthermore, either NPB23 or NPW23 significantly reduced morphine-induced conditioned place preference (CPP) and constipation. We also found that phosphorylation of extracellular-regulated protein kinase (ERK1/2) following morphine was profoundly potentiated by the application of NPB23 or NPW23. Hence, combination of morphine with either NPB23 or NPW23 reduced dose of morphine required for pain relief in inflammatory and neuropathic pain, while effectively prevented some side-effects of morphine.


Assuntos
Analgésicos Opioides/farmacologia , Neuropeptídeos/farmacologia , Dor Nociceptiva/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Ciática/prevenção & controle , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Formaldeído , Células HEK293 , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuropeptídeos/síntese química , Neuropeptídeos/uso terapêutico , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Fosforilação , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Ciática/metabolismo , Ciática/fisiopatologia , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/fisiopatologia
16.
Xenobiotica ; 51(5): 501-512, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33622176

RESUMO

The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored in vitro. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ1R) antagonism and µ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible in vivo impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected.Preliminary in vitro interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings.


Assuntos
Preparações Farmacêuticas , Receptores sigma , Células CACO-2 , Interações Medicamentosas , Humanos , Receptores Opioides mu/agonistas
17.
Basic Clin Pharmacol Toxicol ; 128(6): 731-740, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33533572

RESUMO

Chimeric peptide MCRT (YPFPFRTic-NH2 ) was a multifunctional ligand of opioid and neuropeptide FF (NPFF) receptors and reported to be potentially antalgic in acute tail-flick test. Here, we developed spared nerve injury (SNI) model to explore its efficacy in chronic neuropathic pain. Analgesic tolerance, opioid-induced hyperalgesia and gastrointestinal transit were measured for safety evaluation. Intracerebroventricular (i.c.v.) and intraplantar (i.pl.) injections were conducted as central and peripheral routes, respectively. Results demonstrated that MCRT alleviated neuropathic pain effectively and efficiently, with the ED50 values of 4.93 nmol/kg at the central level and 3.11 nmol/kg at the peripheral level. The antagonist blocking study verified the involvement of mu-, delta-opioid and NPFF receptors in MCRT produced anti-allodynia. Moreover, the separation of analgesia from unwanted effects was preliminarily achieved and that MCRT caused neither analgesic tolerance nor hyperalgesia after chronic i.c.v. administration, nor constipation after i.pl. administration. Notably, the local efficacy of MCRT in SNI mice was about one thousandfold higher than morphine and ten thousandfold higher than pregabalin, indicating a great promise in the future treatment of neuropathic pain.


Assuntos
Analgésicos Opioides/farmacologia , Endorfinas/farmacologia , Neuralgia/tratamento farmacológico , Receptores de Neuropeptídeos/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Animais , Ligantes , Camundongos , Morfina , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/agonistas
18.
J Ethnopharmacol ; 270: 113872, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33485984

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mu opioid receptor (MOR) is mainly a drug target for analgesia. Opioid-like agonists such as morphine have been clinically used for analgesia but have potential adverse effects. MOR antagonists have been demonstrated to alleviate these side effects. Plants (Carthamus tinctorius L, Cynanchum otophyllum C. K. Schneid., Coffea arabica L., Prinsepia utilis Royle and Lepidium meyenii Walp.) and Ganoderma fungi (Ganoderma hainanense J. D. Zhao, Ganoderma capense (Lloyd) Teng, Ganoderma cochlear (Blume et Nees) Bres., Ganoderma resinaceum Boud and Ganoderma applanatum (Pers.) Pat.) are traditional medicines with beneficial effects on immunoregulation, analgesia and the nervous system, but whether MORs are engaged in their effects remains unknown. AIM OF THE STUDY: This work aimed to identify MOR ligands among compounds isolated from the above-mentioned 10 species, and to investigate selectivity against four opioid receptor subtypes. By analyzing the structure-activity relationship and off-target effects, we could provide a new direction for the future development of MOR drugs. MATERIALS AND METHODS: Four opioid receptor subtype models, including MOR, delta (DOR), kappa (KOR) and nop (NOR), were established with a label-free phenotypic dynamic mass redistribution assay to systematically profile the pharmacological properties of known ligands. Then, 82 natural compounds derived from the 10 species were screened against MOR to identify new ligands. The selectivity of the new ligands was characterized against the four subtypes, and off-target effects were also investigated on eight G protein-coupled receptors (GPCRs). RESULTS: The pharmacological properties of known ligands on transfected HEK293T-MOR, HEK293-DOR, HEK293-KOR and HEK293-NOR cell lines were characterized. Seven compounds purified from Ganoderma cochlear (Blume et Nees) Bres. and Carthamus tinctorius L were MOR antagonists with micromolar potency. Among them, compound 35 showed the strongest antagonistic activity on MOR with an IC50 value of 10.0 ± 3.0 µM. To a certain extent, these seven new antagonists, exhibited antagonistic activity on the other opioid receptor subtypes, and they had almost no effect on other GPCRs, including CB1, CB2, M2 and beta2AR. Additionally, a compound from Lepidium meyenii Walp. displayed MOR agonistic activity. CONCLUSIONS: The established screening models opened new avenues for the discovery and evaluation of opioid receptor ligand selectivity. Together, the novel MOR antagonists and agonists will enrich the inventory of MOR ligands and benefit related therapies.


Assuntos
Produtos Biológicos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides/metabolismo , Produtos Biológicos/química , Técnicas Biossensoriais/métodos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Humanos , Ligantes , Receptores Opioides/agonistas , Receptores Opioides/genética , Relação Estrutura-Atividade
19.
Neurosci Lett ; 746: 135651, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33482313

RESUMO

Stress-induced activation of locus coeruleus (LC)-norepinephrine (NE) projections to the prefrontal cortex are thought to promote cognitive responses to stressors. LC activation by stressors is modulated by endogenous opioids that restrain LC activation and facilitate a return to baseline activity upon stress termination. Sex differences in this opioid influence could be a basis for sex differences in stress vulnerability. Consistent with this, we recently demonstrated that µ-opioid receptor (MOR) expression is decreased in the female rat LC compared to the male LC, and this was associated with sexually distinct consequences of activating MOR in the LC on cognitive flexibility. Given that the LC-NE system affects cognitive flexibility through its projections to the medial prefrontal cortex (mPFC), the present study quantified and compared the effects of LC-MOR activation on mPFC neural activity in male and female rats. Local field potential (LFPs) were recorded from the mPFC of freely behaving male and female rats before and following local LC microinjection of the MOR agonist, DAMGO, or vehicle. Intra-LC DAMGO altered the LFP power spectrum selectively in male but not female rats, resulting in a time-dependent increase in the power in delta and alpha frequency bands. LC microinfusion of ACSF had no effect on either sex. Together, the results are consistent with previous evidence for decreased MOR function in the female rat LC and demonstrate that this translates to a diminished effect on cortical activity that can account for sex differences in cognitive consequences. Decreased LC-MOR function in females could contribute to greater stress-induced activation of the LC and increased vulnerability of females to hyperarousal symptoms of stress-related neuropsychiatric pathologies.


Assuntos
Analgésicos Opioides/administração & dosagem , Locus Cerúleo/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Opioides mu/metabolismo , Caracteres Sexuais , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Feminino , Locus Cerúleo/efeitos dos fármacos , Masculino , Microinjeções/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/agonistas , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
20.
J Pharmacol Exp Ther ; 376(3): 374-384, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33443077

RESUMO

Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically because they retain sufficient efficacy to produce therapeutically desirable effects while minimizing undesirable effects. Molecular mechanisms of efficacy are not well understood, so rational drug design to control efficacy is not yet possible; however, receptor theory predicts that fixed-proportion mixtures of an agonist and antagonist for a given receptor can be adjusted to precisely control net efficacy of the mixture in activating that receptor. Moreover, the agonist proportion required to produce different effects provides a quantitative scale for comparing efficacy requirements across those effects. To test this hypothesis, the present study evaluated effectiveness of fixed-proportion agonist/antagonist mixtures to produce in vitro and in vivo effects mediated by µ-opioid receptors (MOR) and cannabinoid type 1 receptors (CB1R). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CB1R agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'-O-(3-[35S]thio)triphosphate binding and an in vivo assay of thermal nociception in mice. For both agonist/antagonist pairs in both assays, increasing agonist proportions produced graded increases in maximal mixture effects, and lower agonist proportions were sufficient to produce in vivo than in vitro effects. These findings support the utility of agonist-antagonist mixtures as a strategy to control net efficacy of receptor activation and to quantify and compare efficacy requirements across a range of in vitro and in vivo endpoints. SIGNIFICANCE STATEMENT: Manipulation of agonist proportion in agonist/antagonist mixtures governs net mixture efficacy at the target receptor. Parameters of agonist/antagonist mixture effects can provide a quantitative metric for comparison of efficacy requirements across a wide range of conditions.


Assuntos
Analgésicos Opioides/farmacologia , Canabinoides/farmacologia , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Camundongos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores
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