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1.
Pharmaceuticals (Basel) ; 14(10)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34681199

RESUMO

Paclitaxel is a chemotherapeutic drug used for cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common major dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. CIPN is accompanied by mechanical and thermal hypersensitivity that resolves within weeks, months, or years after drug termination. To date, there is no available preventive strategy or effective treatment for CIPN due to the fact that its etiology has not been fully explained. It is clear that free radicals are implicated in many neurodegenerative diseases and recent studies have shown the important role of oxidative stress in development of CIPN. Here, we observed how, in rats, the administration of a natural antioxidant such as the bergamot polyphenolic extract (BPF), can play a crucial role in reducing CIPN. Paclitaxel administration induced mechanical allodynia and thermal hyperalgesia, which began to manifest on day seven, and reached its lowest levels on day fifteen. Paclitaxel-induced neuropathic pain was associated with nitration of proteins in the spinal cord including MnSOD, glutamine synthetase, and glutamate transporter GLT-1. This study showed that the use of BPF, probably by inhibiting the nitration of crucial proteins involved in oxidative stress, improved paclitaxel-induced pain behaviors relieving mechanical allodynia, thermal hyperalgesia, thus preventing the development of chemotherapy-induced neuropathic pain.

2.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360719

RESUMO

Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.


Assuntos
Agonistas do Receptor A3 de Adenosina/uso terapêutico , Sinalização do Cálcio/efeitos dos fármacos , Gânglios Espinais , Dor , Receptor A3 de Adenosina/metabolismo , Animais , Astrócitos/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Humanos , Microglia/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia
3.
Mo Med ; 118(4): 327-333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373667

RESUMO

Chronic neuropathic pain is currently a major health issue in U.S. complicated by the lack of non-opioid analgesic alternatives. Our investigations led to the discovery of major signaling pathways involved in the transition of acute to chronic neuropathic pain and the identification of several targets for therapeutic intervention. Our translational approach has facilitated the advancement of novel medicines for chronic neuropathic pain that are in advanced clinical development and clinical trials.


Assuntos
Dor Crônica , Neuralgia , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Humanos , Neuralgia/tratamento farmacológico
5.
Mo Med ; 118(4): 352-357, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373671

RESUMO

G protein-coupled receptors (GPCRs) transmit the signals of a variety of hormones and neurotransmitters and are targets of more than 30% of all FDA-approved drugs. We developed an approach for identifying the endogenous ligands for a family of orphan GPCRs that enables the development of novel therapeutics for the potential treatment of a wide variety of disorders including pain, diabetes, appetitive behaviors, infertility and obesity. With this approach, we have deorphanized five previously orphaned GPCRs.


Assuntos
Obesidade , Humanos , Ligantes
6.
Cephalalgia ; 41(11-12): 1187-1200, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34256650

RESUMO

BACKGROUND: Reactive nitroxidative species, such as nitric oxide but particularly peroxynitrite, have been strongly implicated in pain mechanisms. Targeting peroxynitrite is anti-nociceptive in pain models, but little is known about its role in migraine mechanisms. Given the need to validate novel targets for migraine headache, our objective was to study the potential of reactive nitroxidative species, particularly peroxynitrite, as novel targets for drug discovery and their role in migraine mechanisms. METHODS: We recorded neuronal activity in rats with extracellular electrodes and examined the effects of targeting nitric oxide or peroxynitrite on ongoing and cranial-evoked firing rates of central trigeminocervical neurons. We injected calcitonin gene-related peptide (which produces migraine-like headache in migraineurs) and characterized neuronal responses to cranial stimulation and on behavioral responses to nociceptive periorbital stimulation and determined the effects of targeting reactive nitroxidative species on the mediated changes. RESULTS: L-NAME (nitric oxide synthase inhibitor) and Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride (FeTPPS; peroxynitrite decomposition catalyst) inhibited ongoing and dural-evoked responses of trigeminocervical neurons, without affecting normal facial-cutaneous responses. Calcitonin gene-related peptide caused activation and sensitization of dural-responsive trigeminovascular neurons with hypersensitivity to intracranial and extracranial stimulation, and reduction of periorbital withdrawal thresholds. Only the peroxynitrite decomposition catalyst prevented these neuronal and behavioral nociceptive responses. DISCUSSION: The data support that calcitonin gene-related peptide mediates the underlying neurobiological mechanisms related to the development of migraine-like headache. They also confirm the role of nitric oxide and implicate peroxynitrite production along the trigeminovascular migraine pathway in these mechanisms. The data also support peroxynitrite as a novel and potentially effective target for migraine treatment. The current drug development focus on peroxynitrite decomposition catalysts for chronic pain disorders should therefore extend to migraine.

7.
Neurosci Lett ; 760: 136087, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34182057

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a somatosensory axonopathy in cancer patients receiving any of a variety of widely-use antitumor agents. CIPN can lead to long-lasting neuropathic pain that limits the dose or length of otherwise life-saving cancer therapy. Accumulating evidence over the last two decades indicates that many chemotherapeutic agents cause mitochondrial injury in the peripheral sensory nerves by disrupting mitochondrial structure and bioenergetics, increasing nitro-oxidative stress and altering mitochondrial transport, fission, fusion and mitophagy. The accumulation of abnormal and dysfunctional mitochondria in sensory neurons are linked to axonal growth defects resulting in the loss of intraepidermal nerve fibers in the hands and feet, increased spontaneous discharge and the sensitization of peripheral sensory neurons that provoke and promote changes in the central nervous system that establish a chronic neuropathic pain state. This has led to the propose mitotoxicity theory of CIPN. Strategies that improve mitochondrial function have shown success in preventing and reversing CIPN in pre-clinical animal models and have begun to show some progress toward translation to the clinic. In this review, we will review the evidence for, the causes and effects of and current strategies to target mitochondrial dysfunction in CIPN.

9.
J Neurosci Res ; 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075613

RESUMO

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A3 adenosine receptor (A3 AR) in opioid analgesic tolerance. Intrathecal administration of the A3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A3 AR expression was not affected. Collectively, our findings indicate that spinal A3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

10.
Neuron ; 109(9): 1426-1429, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33957072

RESUMO

Chronic pain is a disabling disease with limited treatment options. While animal models have revealed important aspects of pain neurobiology, therapeutic translation of this knowledge requires our understanding of these cells and networks of pain in humans. We propose a multi-institutional collaboration to rigorously and ethically address this challenge.


Assuntos
Dor Crônica , Colaboração Intersetorial , Humanos
11.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34043767

RESUMO

Cocaine- and amphetamine-regulated transcript encodes an eponymous peptide, CARTp, which exerts diverse pharmacologic actions in the central and peripheral nervous systems, as well as in several endocrine organs, including pancreas. Here we review those diverse actions, the physiological relevance of which had remained unestablished until recently. With the identification of a CARTp receptor, GPR160, the physiologic importance and therapeutic potential of CARTp or analogs are being revealed. Not only is the CARTp-GPR160 interaction essential for the circadian regulation of appetite and thirst but also for the transmission of nerve injury-induced pain. Molecular approaches now are uncovering additional physiologically relevant actions and the development of acute tissue-specific gene compromise approaches may reveal even more physiologically relevant actions of this pluripotent ligand/receptor pair.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Humanos , Pesquisa Médica Translacional
13.
Physiol Behav ; 235: 113380, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33705816

RESUMO

The existence of the peptide encoded by the cocaine- and amphetamine-regulated transcript (Cartpt) has been recognized since 1981, but it was not until 1995, that the gene encoding CART peptide (CART) was identified. With the availability of the predicted protein sequence of CART investigators were able to identify sites of peptide localization, which then led to numerous approaches attempting to clarify CART's multiple pharmacologic effects and even provide evidence of potential physiologic relevance. Although not without controversy, a picture emerged of the importance of CART in ingestive behaviors, reward behaviors and even pain sensation. Despite the wealth of data hinting at the significance of CART, in the absence of an identified receptor, the full potential for this peptide or its analogs to be developed into therapeutic agents remained unrealized. There was evidence favoring the action of CART via a G protein-coupled receptor (GPCR), but despite multiple attempts the identity of that receptor eluded investigators until recently. Now with the identification of the previously orphaned GPCR, GPR160, as a receptor for CART, focus on this pluripotent neuropeptide will in all likelihood experience a renaissance and the potential for the development of pharmcotherapies targeting GPR160 seems within reach.


Assuntos
Cocaína , Neuropeptídeos , Comportamento Alimentar , Proteínas do Tecido Nervoso/genética , Recompensa
14.
J Med Chem ; 64(8): 5099-5122, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33787273

RESUMO

A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.


Assuntos
Piperidinas/química , Antagonistas do Receptor Purinérgico P2/química , Receptores Purinérgicos P2/metabolismo , Animais , Sítios de Ligação , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia/tratamento farmacológico , Piperidinas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Solubilidade , Relação Estrutura-Atividade , Triazóis/química
15.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33621215

RESUMO

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Linfócitos T CD4-Positivos/imunologia , Gânglios Espinais/imunologia , Interleucina-10/imunologia , Neuralgia/tratamento farmacológico , Neurônios/imunologia , Receptor A3 de Adenosina/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Gânglios Espinais/patologia , Interleucina-10/genética , Camundongos , Camundongos Knockout , Neuralgia/genética , Neuralgia/imunologia , Neuralgia/patologia , Neurônios/patologia , Receptor A3 de Adenosina/genética
16.
Antioxidants (Basel) ; 9(12)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339104

RESUMO

In clinical practice, inflammatory pain is an important, unresolved health problem, despite the utilization of non-steroidal anti-inflammatory drugs (NSAIDs). In the last decade, different studies have proven that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in the development and maintenance of inflammatory pain and hyperalgesia via the post-translation modification of key proteins, such as manganese superoxide dismutase (MnSOD). It is well-known that inducible cyclooxygenase 2 (COX-2) plays a crucial role at the beginning of the inflammatory response by converting arachidonic acid into proinflammatory prostaglandin PGE2 and then producing other proinflammatory chemokines and cytokines. Here, we investigated the impact of oxidative stress on COX-2 and prostaglandin (PG) pathways in paw exudates, and we studied how this mechanism can be reversed by using antioxidants during hyperalgesia in a well-characterized model of inflammatory pain in rats. Our results reveal that during the inflammatory state, induced by intraplantar administration of carrageenan, the increase of PGE2 levels released in the paw exudates were associated with COX-2 nitration. Moreover, we showed that the inhibition of ROS with Mn (III) tetrakis (4-benzoic acid) porphyrin(MnTBAP) antioxidant prevented COX-2 nitration, restored the PGE2 levels, and blocked the development of thermal hyperalgesia.

17.
J Neuroinflammation ; 17(1): 339, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33183330

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. METHODS: Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. RESULTS: When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4-5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. CONCLUSION: Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

18.
Antioxidants (Basel) ; 9(11)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182469

RESUMO

Neuropathic pain is a chronic painful disease. Data have shown that reactive oxygen species (ROS) are implicated in chronic pain. Particularly, the enhanced ROS production alters the mitochondrial genome and proteome through the accumulation of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Sirtuin 3 (SIRT3) is a mitochondrial protein and its activity can reduce ROS levels by modulating key antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Here, we evaluated the role of SIRT3 in the maintenance of basal levels of ROS in a model of chronic constriction injury (CCI) of the sciatic nerve and the protective effects of a natural antioxidant, the bergamot polyphenolic fraction (BPF). Rats were exposed to CCI of the sciatic nerve in the presence or absence of BPF (25-75 mg/kg). Level of acetylation, post-translational modulation on cysteine residues of proteins by HNE and SIRT3 activation, were detected in the spinal cord through western blotting, WES methodology and enzymatic assays. Our results reported that SIRT3 carbonylation and therefore its inactivation contributes to mitochondrial MnSOD hyperacetylation during CCI induced neuropathic pain in rats. In particular, we have demonstrated a close relation between oxidative stress, hyperalgesia, allodynia and sirtuins inactivation reverted by BPF administration.

19.
Trends Pharmacol Sci ; 41(11): 851-867, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33010954

RESUMO

Chronic pain is a life-altering condition affecting millions of people. Current treatments are inadequate and prolonged therapies come with severe side effects, especially dependence and addiction to opiates. Identification of non-narcotic analgesics is of paramount importance. Preclinical and clinical studies suggest that sphingolipid metabolism alterations contribute to neuropathic pain development. Functional sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) antagonists, such as FTY720/fingolimod, used clinically for non-pain conditions, are emerging as non-narcotic analgesics, supporting the repurposing of fingolimod for chronic pain treatment and energizing drug discovery focused on S1P signaling. Here, we summarize the role of S1P in pain to highlight the potential of targeting the S1P axis towards development of non-narcotic therapeutics, which, in turn, will hopefully help lessen misuse of opioid pain medications and address the ongoing opioid epidemic.


Assuntos
Analgésicos não Narcóticos/farmacologia , Dor Crônica/tratamento farmacológico , Lisofosfolipídeos/metabolismo , Manejo da Dor/métodos , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Esfingosina/análogos & derivados , Animais , Dor Crônica/metabolismo , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo
20.
J Neuroinflammation ; 17(1): 314, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092620

RESUMO

Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1ß (IL-1ß); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

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