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The pharmacological or toxicological activities of the degradation products of drug candidates have been unaddressed during the drug development process. Ischemic stroke accounts for 80% of all strokes and is responsible for considerable mortality and disability worldwide. Despite decades of research on neuroprotective agents, tissue plasminogen activators (t-PA), a thrombolytic agent, remains the only approved acute stroke pharmacological therapy. NXY-059, a free radical scavenger, exhibited striking neuroprotective properties in preclinical models and met all the criteria established by the Stroke Academic Industry Roundtable (STAIR) for a neuroprotective agent. In phase 3 clinical trials, NXY-059 exhibited significant neuroprotective effects in one trial (SAINT-I), but not in the second (SAINT-II). Some have hypothesized that N-t-butyl hydroxylamine (NtBHA), a breakdown product of NXY-059 was the actual neuroprotective agent in SAINT-I and that changes to the formulation of NXY-059 to prevent its breakdown to NtBHA in SAINT -II was the reason for the lack of efficacy. We evaluated the neuroprotective effect of NtBHA in N-methyl-D-aspartate (NMDA)-treated primary neurons and in rat focal cerebral ischemia. NtBHA significantly attenuated infarct volume in rat transient focal ischemia, and attenuated NMDA-induced cytotoxicity in primary cortical neurons. NtBHA also reduced free radical generation and exhibited mitochondrial protection.
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l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. We hypothesized that d-carnosine, which is not a substrate for carnosinases, may have a better pharmacological profile and may be more efficacious at lower doses than l-carnosine. To test our hypothesis, we explored the comparative pharmacokinetics and neuroprotective properties of d- and L-carnosine in acute ischaemic stroke in mice. We initially investigated the pharmacokinetics of d- and L-carnosine in serum and brain after intravenous (IV) injection in mice. We then investigated the comparative efficacy of d- and l-carnosine in a mouse model of transient focal cerebral ischemia followed by in vitro testing against excitotoxicity and free radical generation using primary neuronal cultures. The pharmacokinetics of d- and l-carnosine were similar in serum and brain after IV injection in mice. Both d- and l-carnosine exhibited similar efficacy against mouse focal cerebral ischemia. In vitro studies in neurons showed protection against excitotoxicity and the accumulation of free radicals. d- and l-carnosine exhibit similar pharmacokinetics and have similar efficacy against experimental stroke in mice. Since humans have far higher levels of carnosinases, d-carnosine may have more favorable pharmacokinetics in future human studies.
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Carnosina/administración & dosificación , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Neuronas/citología , Fármacos Neuroprotectores/administración & dosificación , Animales , Química Encefálica , Carnosina/química , Carnosina/farmacocinética , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inyecciones Intravenosas , Accidente Cerebrovascular Isquémico/sangre , Masculino , Ratones , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Cultivo Primario de CélulasRESUMEN
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.
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Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , AnimalesRESUMEN
PURPOSE OF REVIEW: Migraine is an extremely incapacitating collection of neurological symptoms that usually includes a severe, throbbing, recurring pain on one side of the head. The World Health Organization ranks migraine as the third most prevalent disease and the seventh commonest primary pain condition in the world. Trigeminovascular-mediated central sensitization has been implicated in the development of migraine symptoms including pain following light touch. This review explores the activation and sensitization of the brain systems that have emerged from recent studies and that contribute to migraine. RECENT FINDINGS: A number of pathophysiological mechanisms have been implicated in the development of migraine and other primary headache disorders. Neuroimaging techniques used to identify both structural and functional features of the brain in migraineurs have helped identify brain regions that are active during or in between migraine attacks, with particular emphasis on those areas relevant to pain pathways, including the hypothalamus and periaqueductal grey. SUMMARY: Several key studies have helped address the long-standing debate over whether migraine originates from vascular or neuronal dysfunction and now support that migraine is a neurological disorder. However, a complete understanding of the central nervous system dysfunction underlying this condition has yet to be elucidated.
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Trastornos Migrañosos/fisiopatología , Tronco Encefálico/fisiopatología , Sensibilización del Sistema Nervioso Central/fisiología , Cefalalgia Histamínica/diagnóstico por imagen , Cefalalgia Histamínica/fisiopatología , Depresión de Propagación Cortical/fisiología , Trastornos de Cefalalgia/diagnóstico por imagen , Trastornos de Cefalalgia/fisiopatología , Humanos , Trastornos Migrañosos/diagnóstico por imagen , Neocórtex/fisiopatología , Ganglio del Trigémino/fisiopatología , Nervio Trigémino/fisiopatología , Vasodilatación/fisiologíaRESUMEN
This article was updated to correct an error in figure 1 introduced during the production process.
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The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.
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Núcleo Amigdalino Central/efectos de los fármacos , Dolor/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Estrés Fisiológico/fisiología , Analgésicos Opioides/farmacología , Animales , Capsaicina/farmacología , Núcleo Amigdalino Central/metabolismo , Dinorfinas/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/metabolismo , Morfina/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/etiología , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismoRESUMEN
Migraine is a common and disabling primary headache disorder with a significant socioeconomic burden. The management of migraine is multifaceted and is generally dichotomized into acute and preventive strategies, with several treatment modalities. The aims of acute pharmacological treatment are to rapidly restore function with minimal recurrence, with the avoidance of side effects. The choice of pharmacological treatment is individualized, and is based on the consideration of the characteristics of the migraine attack, the patient's concomitant medical problems, and treatment preferences. Notwithstanding, a good understanding of the pharmacodynamic and pharmacokinetic properties of the various drug options is essential to guide therapy. The current approach and concepts relevant to the acute pharmacological treatment of migraine will be explored in this review.
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Trastornos Migrañosos/tratamiento farmacológico , Acetaminofén/uso terapéutico , Analgésicos Opioides/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Antagonistas de Dopamina/uso terapéutico , Alcaloides de Claviceps/uso terapéutico , Humanos , Trastornos Migrañosos/fisiopatología , Triptaminas/uso terapéuticoRESUMEN
Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.
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Trastornos Migrañosos , Antagonistas de Narcóticos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Naltrexona/análogos & derivados , Naltrexona/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Bone metastases occur frequently in advanced breast, lung, and prostate cancer, with approximately 70% of patients affected. Pain is a major symptom of bone metastases, and current treatments may be inadequate or have unacceptable side effects. The mechanisms that drive cancer-induced bone pain are not fully understood; however, it is known that there is sensitization of both peripheral bone afferents and central spinal circuits. It is well established that the N-methyl-D-aspartate receptor plays a major role in the pathophysiology of pain hypersensitivity. Inhibition of the non-receptor tyrosine kinase Src controls N-methyl-D-aspartate receptor activity and inhibiting Src reduces the hypersensitivity associated with neuropathic and inflammatory pains. As Src is also implicated in osteoclastic bone resorption, we have investigated if inhibiting Src ameliorates cancer-induced bone pain. We have tested this hypothesis using an orally bioavailable Src inhibitor (saracatinib) in a rat model of cancer-induced bone pain. RESULTS: Intra-tibial injection of rat mammary cancer cells (Mammary rat metastasis tumor cells -1), but not vehicle, in rats produced hindpaw hypersensitivity to thermal and mechanical stimuli that was maximal after six days and persisted for at least 13 days postinjection. Daily oral gavage with saracatinib (20 mg/kg) beginning seven days after intra-tibial injection reversed the thermal hyperalgesia but not the mechanical allodynia. The analgesic mechanisms of saracatinib appear to be due to an effect on the nervous system as immunoblotting of L2-5 spinal segments showed that mammary rat metastasis tumor cells-1 injection induced phosphorylation of the GluN1 subunit of the N-methyl-D-aspartate receptor, indicative of receptor activation, and this was reduced by saracatinib. Additionally, histology showed no anti-tumor effect of saracatinib at any dose and no significant effect on bone preservation. CONCLUSIONS: This is the first demonstration that Src plays a role in the development of cancer-induced bone pain and that Src inhibition represents a possible new analgesic strategy for patients with bone metastases.
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Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Dolor en Cáncer/complicaciones , Dolor en Cáncer/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Familia-src Quinasas/antagonistas & inhibidores , Animales , Conducta Animal , Benzodioxoles/farmacocinética , Benzodioxoles/farmacología , Benzodioxoles/uso terapéutico , Neoplasias Óseas/fisiopatología , Remodelación Ósea/efectos de los fármacos , Resorción Ósea/complicaciones , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/fisiopatología , Dolor en Cáncer/fisiopatología , Modelos Animales de Enfermedad , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Médula Espinal/patología , Familia-src Quinasas/metabolismoRESUMEN
Pain is more than merely nociception and response, but rather it encompasses emotional, behavioral and cognitive components that make up the pain experience. With the recent advances in imaging techniques, we now understand that nociceptive inputs can result in the activation of complex interactions among central sites, including cortical regions that are active in cognitive, emotional and reward functions. These sites can have a bimodal influence on the serotonergic and noradrenergic descending pain modulatory systems via communications among the periaqueductal gray, rostral ventromedial medulla and pontine noradrenergic nuclei, ultimately either facilitating or inhibiting further nociceptive inputs. Understanding these systems can help explain the emotional and cognitive influences on pain perception and placebo/nocebo effects, and can help guide development of better pain therapeutics.
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Encéfalo/fisiopatología , Nocicepción/fisiología , Dolor/fisiopatología , Neuronas Adrenérgicas/fisiología , Humanos , Vías Nerviosas/fisiopatología , Neuronas/fisiología , Efecto Placebo , Neuronas Serotoninérgicas/fisiologíaRESUMEN
We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A's biological activity, is not necessary, and that a type I ß-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naïve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.
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Dinorfinas/farmacología , Receptores de Bradiquinina/metabolismo , Médula Espinal/efectos de los fármacos , Animales , Dinorfinas/química , Espectroscopía de Resonancia Magnética , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: The objective of this article is to evaluate electrically evoked thresholds for cortical spreading depression (CSD) and stress-induced activation of trigeminal afferents in a rat model of medication-overuse headache (MOH). METHODS: Sumatriptan or saline was delivered subcutaneously by osmotic minipump for six days to Sprague-Dawley rats. Two weeks after pump removal, animals were anesthetized and recording/stimulating electrodes implanted. The animals were pretreated with vehicle or topiramate followed by graded electrical stimulation within the visual cortex. CSD events were identified by decreased EEG amplitude and DC potential shift. Additional unanesthetized sumatriptan or saline-pretreated rats were exposed to bright light environmental stress and periorbital and hindpaw withdrawal thresholds were measured. Following CSD stimulation or environmental stress, immunohistochemical staining for Fos in the trigeminal nucleus caudalis (TNC) was performed. RESULTS: Sumatriptan pre-exposure significantly decreased electrical stimulation threshold to generate a CSD event. Topiramate normalized the decreased CSD threshold as well as stress-induced behavioral withdrawal thresholds in sumatriptan-treated rats compared to saline-treated animals. Moreover, CSD and environmental stress increased Fos expression in the TNC of sumatriptan-treated rats, and these effects were blocked by topiramate. Environmental stress did not elicit cutaneous allodynia or elevate TNC Fos expression in saline-treated rats. CONCLUSIONS: A previous period of sumatriptan exposure produced long-lasting increased susceptibility to evoked CSD and environmental stress-induced activation of the TNC that was prevented by topiramate. Lowered CSD threshold, and enhanced consequences of CSD events (increased activation of TNC), may represent an underlying biological mechanism of MOH related to triptans.
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Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Modelos Animales de Enfermedad , Cefaleas Secundarias/fisiopatología , Sumatriptán/toxicidad , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Humanos , Infusiones Subcutáneas , Masculino , Ratas Sprague-Dawley , Factores de Riesgo , Umbral Sensorial/efectos de los fármacos , Umbral Sensorial/fisiología , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatología , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/fisiopatologíaRESUMEN
OBJECTIVE: Preclinical evaluation of headache by behavioral assessment of reward from pain relief. METHODS: Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. RESULTS: Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury. INTERPRETATION: Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.
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Conducta Animal/efectos de los fármacos , Cefalea/tratamiento farmacológico , Lidocaína/farmacología , Bloqueo Nervioso , Animales , Conducta Animal/fisiología , Giro del Cíngulo/efectos de los fármacos , Cefalea/inducido químicamente , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Lidocaína/administración & dosificación , Masculino , Microinyecciones , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
UNLABELLED: Neuropathic pain is frequently characterized by spontaneous pain (ie, pain at rest) and, in some cases, by cold- and touch-induced allodynia. Mechanisms underlying the chronicity of neuropathic pain are not well understood. Rats received spinal nerve ligation (SNL) and were monitored for tactile and thermal thresholds. While heat hypersensitivity returned to baseline levels within approximately 35 to 40 days, tactile hypersensitivity was still present at 580 days after SNL. Tactile hypersensitivity at post-SNL day 60 (D60) was reversed by microinjection of 1) lidocaine; 2) a cholecystokinin 2 receptor antagonist into the rostral ventromedial medulla; or 3) dorsolateral funiculus lesion. Rostral ventromedial medulla lidocaine at D60 or spinal ondansetron, a 5-hydroxytryptamine 3 antagonist, at post-SNL D42 produced conditioned place preference selectively in SNL-treated rats, suggesting long-lasting spontaneous pain. Touch-induced FOS was increased in the spinal dorsal horn of SNL rats at D60 and prevented by prior dorsolateral funiculus lesion, suggesting that long-lasting tactile hypersensitivity depends upon spinal sensitization, which is mediated in part by descending facilitation, in spite of resolution of heat hypersensitivity. PERSPECTIVE: These data suggest that spontaneous pain is present for an extended period of time and, consistent with likely actions of clinically effective drugs, is maintained by descending facilitation.
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Vías Aferentes/fisiología , Neuralgia/fisiopatología , Umbral del Dolor/fisiología , Vías Aferentes/efectos de los fármacos , Anestésicos Locales/farmacología , Anestésicos Locales/efectos de la radiación , Anestésicos Locales/uso terapéutico , Animales , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Antagonistas de Hormonas/farmacología , Antagonistas de Hormonas/uso terapéutico , Hiperalgesia/fisiopatología , Lidocaína/farmacología , Lidocaína/uso terapéutico , Masculino , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/fisiología , Neuralgia/tratamiento farmacológico , Proteínas Oncogénicas v-fos/metabolismo , Ondansetrón/farmacología , Ondansetrón/uso terapéutico , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/uso terapéutico , Nervios Espinales/lesiones , Factores de TiempoRESUMEN
Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.
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Péptido Relacionado con Gen de Calcitonina/metabolismo , Hiperalgesia/metabolismo , Neuropéptidos/fisiología , Médula Espinal/metabolismo , Animales , Anisomicina/farmacología , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptidos/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Puromicina/farmacología , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Sustancia P/metabolismo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. RESULTS: To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment. CONCLUSIONS: These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.
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Proteínas Quinasas Activadas por AMP/metabolismo , Dolor Agudo/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Receptoras Sensoriales/enzimología , Estilbenos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Dolor Agudo/enzimología , Dolor Agudo/patología , Animales , Dolor Crónico/enzimología , Dolor Crónico/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Factor 4F Eucariótico de Iniciación/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Hiperalgesia/complicaciones , Hiperalgesia/metabolismo , Hiperalgesia/patología , Interleucina-6/administración & dosificación , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Dolor Postoperatorio/complicaciones , Dolor Postoperatorio/patología , Biosíntesis de Proteínas/efectos de los fármacos , Resveratrol , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Estilbenos/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Factores de Tiempo , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/patologíaRESUMEN
A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α(2) adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
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Dolor Crónico/fisiopatología , Bulbo Raquídeo/fisiología , Inhibición Neural/fisiología , Neuralgia/fisiopatología , Umbral del Dolor/fisiología , Médula Espinal/fisiología , Animales , Modelos Animales de Enfermedad , Vías Eferentes/efectos de los fármacos , Vías Eferentes/fisiología , Bulbo Raquídeo/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Médula Espinal/patologíaRESUMEN
BACKGROUND: Cortical spreading depression (CSD) is a wave of depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex. CSD is believed to be the underlying mechanism of aura in migraine; however, whether CSD can elicit pain associated with migraine headache is unclear. METHODS: Awake, freely moving rats were monitored for both CSD events and behavioral responses resulting from dural-cortical pinprick and/or KCl injection to the occipital cortex. RESULTS: We observed tactile allodynia of the face and hindpaws, as well as enhanced Fos expression within the trigeminal nucleus caudalis (TNC) following CSD induced by KCl injection into the cortex, but not by pinprick. Application of KCl onto the dura elicited cutaneous allodynia and increased Fos staining in the TNC but did not elicit CSD events. CONCLUSIONS: These data suggest that sustained activation of trigeminal afferents that may be required to establish cutaneous allodynia may not occur following CSD events in normal animals.
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Depresión de Propagación Cortical/fisiología , Hiperalgesia/fisiopatología , Núcleo Caudal del Trigémino/fisiología , Animales , Electrofisiología , Masculino , Movimiento/fisiología , Ratas , Ratas Sprague-Dawley , Piel/inervación , Tacto/fisiología , Nervio Trigémino/fisiologíaRESUMEN
Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain.
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Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Quinolinas/uso terapéutico , Animales , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Trastornos Migrañosos/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
PURPOSE OF REVIEW: An impediment to the investigation of mechanisms that drive headache is the inability of preclinical models to measure headache. Migraine attacks are associated with the development of cutaneous allodynia in some patients. Such cutaneous allodynia suggests a state of 'central sensitization' of pain transmission pathways and may additionally reflect the engagement of descending facilitation from pain modulatory circuits. For this reason, cutaneous allodynia has been measured in animal models as a surrogate of marker that may be relevant to headache. Overuse of antimigraine medications can promote an increase in the frequency and intensity of headache, a syndrome termed medication overuse headache (MOH). The mechanisms leading to MOH are not known, but may involve the processes of amplification including central sensitization and descending facilitation. This review explores potential mechanistic insights that have emerged from such studies and that could contribute to MOH. RECENT FINDINGS: Development of MOH has been recently associated with long-lasting adaptive changes that occur within the peripheral and central nervous systems. Preclinical studies have shown that repeated or continuous treatment with antimigraine drugs result in persistent upregulation of neurotransmitters within the orofacial division of the trigeminal ganglia and in development of cutaneous allodynia in response to migraine triggers, even weeks after discontinuation of the antimigraine drug. Additionally, descending facilitation is critical for the expression of cutaneous allodynia and may mask the expression of diffuse noxious inhibitory controls. SUMMARY: Medication-induced persistent pronociceptive adaptations might be responsible for lowering the threshold and amplifying the response to migraine triggers leading to increased frequency of headache attacks.