RESUMEN
While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving "analgesic" therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood-brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.
Asunto(s)
Analgesia/métodos , Analgésicos/administración & dosificación , Encéfalo/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Dolor/tratamiento farmacológico , Médula Espinal/efectos de los fármacos , Analgésicos/metabolismo , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/metabolismo , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/metabolismo , Antidepresivos/administración & dosificación , Antidepresivos/metabolismo , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Humanos , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Dolor/metabolismo , Manejo del Dolor/métodos , Médula Espinal/metabolismoRESUMEN
Neuropathic pain is a complex disorder associated with emotional and cognitive deficits that may impair nociceptive manifestations. There is high inter-individual variability in the manifestations of human neuropathic pain, which largely depends on personality traits. We aim to identify the influence of different behavioral traits in the inter-individual vulnerability to neuropathic pain manifestations using behavioral, electrophysiological and genetic approaches. We first selected mice with extreme social and emotional traits and look for correlation with the spontaneous neuronal activity in the central amygdala. Neuropathic pain was induced to these mice to evaluate the influence of behavioral traits on nociceptive manifestations and gene expression profiles in the amygdala. Our results show an association of the spontaneous central amygdala neuronal activity with the sociability behavior. We demonstrate that low sociable, high anxious and low depressive phenotypes develop enhanced nociceptive hypersensitivity after nerve injury. However, greater emotional alterations and cognitive impairment are observed in high sociable, anxious-like and depressive-like mice, indicating that nociceptive, emotional and cognitive manifestations of neuropathic pain do not correlate with each other. Gene analyses identify high Pdyn and Il6 levels in the amygdala as indicative of enhanced nociceptive hypersensitivity and reveal an association between high Gadd45 expression and attenuated emotional and cognitive manifestations of neuropathic pain.
Asunto(s)
Cognición/fisiología , Emociones/fisiología , Individualidad , Neuralgia/fisiopatología , Neuralgia/psicología , Dolor Nociceptivo/psicología , Animales , Conducta Animal , Proteínas de Ciclo Celular/biosíntesis , Núcleo Amigdalino Central/metabolismo , Núcleo Amigdalino Central/fisiología , Encefalinas/metabolismo , Expresión Génica , Interleucina-6/metabolismo , Masculino , Ratones , Neuralgia/complicaciones , Dolor Nociceptivo/complicaciones , Precursores de Proteínas/metabolismo , Conducta SocialRESUMEN
OBJECTIVE: Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain. DESIGN: The monoiodoacetate (MIA) model of OA was investigated at early (2-6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to cartilage degradation. Electrophysiological single-unit recordings were taken from spinal wide dynamic range (WDR) neurons to investigate Diffuse Noxious Inhibitory Controls (DNIC) as a marker of potential changes in descending controls. Immunohistochemistry was performed on dorsal root ganglion (DRG) neurons to assess any MIA induced neuronal damage. Furthermore, qPCR was used to measure levels of glia cells and cytokines in the dorsal horn. RESULTS: Both MIA groups develop pain-like behaviour but only late phase (LP) animals display extensive cartilage degradation. Early phase animals have a normally functioning DNIC system but there is a loss of DNIC in LP animals. We found no evidence for neuronal damage caused by MIA in either group, yet an increase in IL-1ß mRNA in the dorsal horn of LP animals. CONCLUSION: The loss of DNIC in LP MIA animals suggests an imbalance in inhibitory and facilitatory descending controls, and a rise in the mRNA expression of IL-1ß mRNA suggest the development of central sensitisation. Therefore, the pain associated with OA in LP animals may not be attributed to purely peripheral mechanisms.
Asunto(s)
Cartílago Articular/patología , Ganglios Espinales/metabolismo , Interleucina-1beta/metabolismo , Articulación de la Rodilla/patología , Osteoartritis de la Rodilla/diagnóstico , Animales , Artralgia/diagnóstico , Artralgia/etiología , Cartílago Articular/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/patología , Inmunohistoquímica , Ácido Yodoacético/toxicidad , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/metabolismo , Masculino , Osteoartritis de la Rodilla/inducido químicamente , Osteoartritis de la Rodilla/complicaciones , Ratas , Ratas Sprague-DawleyRESUMEN
Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Osteoartritis/metabolismo , Osteoartritis/terapia , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Médula Espinal/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ácido Yodoacético , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Norepinefrina/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Médula Espinal/efectos de los fármacosRESUMEN
Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α2 -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT3 receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways.
Asunto(s)
Plasticidad Neuronal , Dolor/fisiopatología , Tractos Piramidales/fisiología , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiología , Humanos , Nocicepción , Dolor/tratamiento farmacológico , Dolor/metabolismo , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/metabolismoRESUMEN
BACKGROUND: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. METHODS: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. RESULTS: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. CONCLUSIONS: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. SIGNIFICANCE: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.
Asunto(s)
Control Inhibidor Nocivo Difuso/fisiología , Neuralgia/fisiopatología , Serotonina/fisiología , Animales , Control Inhibidor Nocivo Difuso/efectos de los fármacos , Fluoxetina/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fenoles/farmacología , Prilocaína/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Sulfonamidas/farmacologíaRESUMEN
Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS.
Asunto(s)
Vías Aferentes/fisiología , Encéfalo/fisiología , Estimulación Eléctrica/métodos , Potenciales Evocados Somatosensoriales/fisiología , Dolor/fisiopatología , Piel/inervación , Adulto , Capsaicina/toxicidad , Sensibilización del Sistema Nervioso Central/fisiología , Electroencefalografía , Femenino , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Masculino , Nociceptores/fisiología , Dolor/inducido químicamente , Dimensión del Dolor , Curva ROC , Tiempo de Reacción/fisiología , Relación Señal-Ruido , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Low back pain (LBP) is one of the most common chronic pain conditions. This paper reviews the available literature on the role of neuropathic mechanisms in chronic LBP and discusses implications for its clinical management, with a particular focus on pharmacological treatments. DATABASES AND DATA TREATMENT: Literature searches were performed in PubMed, key pain congresses and ProQuest Dialog to identify published evidence on neuropathic back pain and its management. All titles were assessed for relevant literature. RESULTS: Chronic LBP comprises both nociceptive and neuropathic components, however, the neuropathic component appears under-recognized and undertreated. Neuropathic pain (NP) is challenging to manage. Many patients with chronic LBP have pain that is refractory to existing treatments. Typically, less than half of patients experience clinically meaningful analgesia with oral pharmacotherapies; these are also associated with risks of adverse effects. Paracetamol and NSAIDs, although widely used for LBP, are unlikely to ameliorate the neuropathic component and data on the use of NP medications such as antidepressants and gabapentin/pregabalin are limited. While there is an unmet need for improved treatment options, recent data have shown tapentadol to have efficacy in the neuropathic component of LBP, and studies suggest that the capsaicin 8% patch and lidocaine 5% medicated plaster, topical analgesics available for the treatment of peripheral NP, may be a valuable additional approach for the management of neuropathic LBP. CONCLUSIONS: Chronic LBP often has an under-recognized neuropathic component, which can be challenging to manage, and requires improved understanding and better diagnosis and treatment. WHAT DOES THIS REVIEW ADD?: Increased recognition and improved understanding of the neuropathic component of low back pain raises the potential for the development of mechanism-based therapies. Open and retrospective studies suggest that agents like tapentadol and topical analgesics - such as the capsaicin 8% patch and the lidocaine 5% medicated plaster - may be effective options for the treatment of neuropathic low back pain in defined patient groups.
Asunto(s)
Analgésicos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Dolor Crónico/diagnóstico , Dolor Crónico/etiología , Humanos , Dolor de la Región Lumbar/diagnóstico , Dolor de la Región Lumbar/etiología , Neuralgia/diagnóstico , Neuralgia/etiologíaRESUMEN
Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 µg/50 µl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 °C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.
Asunto(s)
Caveolina 2/metabolismo , Potenciales Evocados/fisiología , Hiperalgesia/etiología , Neuronas/efectos de los fármacos , Osteoartritis/complicaciones , Animales , Bloqueadores de los Canales de Calcio/uso terapéutico , Modelos Animales de Enfermedad , Potenciales Evocados/efectos de los fármacos , Lateralidad Funcional , Hiperalgesia/tratamiento farmacológico , Indoles/uso terapéutico , Ácido Yodoacético/toxicidad , Masculino , Osteoartritis/inducido químicamente , Osteoartritis/patología , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estimulación Eléctrica Transcutánea del Nervio , Triazoles/uso terapéutico , omega-Conotoxinas/uso terapéuticoRESUMEN
Maladaptive plasticity within the dorsal horn (DH) of the spinal cord is a key substrate for development of neuropathic pain following peripheral nerve injury. Advances in genetic engineering, tracing techniques and opto-genetics are leading to a much better understanding of the complex circuitry of the spinal DH and the radical changes evoked in such circuitry by nerve injury. These changes can be viewed at multiple levels including: synaptic remodeling including enhanced excitatory and reduced inhibitory drive, morphological and electrophysiological changes which are observed both to primary afferent inputs as well as DH neurons, and ultimately circuit-level rewiring which leads to altered connectivity and aberrant processing of sensory inputs in the DH. The DH should not be seen in isolation but is subject to important descending modulation from the brainstem, which is further dysregulated by nerve injury. Understanding which changes relate to specific disease-states is essential, and recent work has aimed to stratify patient populations in a mechanistic fashion. In this review we will discuss how such pathophysiological mechanisms may lead to the distressing sensory phenomena experienced by patients suffering neuropathic pain, and the relationship of such mechanisms to current and potential future treatment modalities.
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Neuralgia/fisiopatología , Plasticidad Neuronal/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Asta Dorsal de la Médula Espinal/fisiopatología , Animales , Humanos , Neuralgia/etiología , Neuralgia/patología , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/patología , Asta Dorsal de la Médula Espinal/patologíaRESUMEN
Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Ganglios Espinales/patología , Indoles/farmacología , Traumatismos de los Nervios Periféricos/patología , Células Receptoras Sensoriales/efectos de los fármacos , Nervios Espinales/patología , Triazoles/farmacología , Acetona/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Hiperalgesia/fisiopatología , Indoles/química , Masculino , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Triazoles/química , omega-Conotoxinas/farmacologíaRESUMEN
Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48°C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48°C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48°C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48°C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45°C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45°C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in osteoarthritic pain.
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Analgésicos/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Osteoartritis/metabolismo , Osteoartritis/fisiopatología , Bloqueadores de los Canales de Sodio/uso terapéutico , Análisis de Varianza , Compuestos de Anilina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Lateralidad Funcional , Furanos/uso terapéutico , Hiperalgesia/fisiopatología , Laminectomía , Osteoartritis/tratamiento farmacológico , Dimensión del Dolor , Ratas , Ratas Sprague-DawleyRESUMEN
Pain is a common and debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of molecular events, including mechanisms observed in inflammatory and neuropathic pain states, but also changes unique for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7R antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity-specific way. Spinal application of 0.4-mg/kg and 1.2-mg/kg A839977 significantly reduced the evoked responses to high-intensity mechanical and thermal stimulation, whereas no effect was seen in response to low-intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naïve or sham animals. In awake animals, 40-mg/kg A839977 (i.p.) significantly reduced both early- and late-stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals. The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous target compared to traditional analgesics.
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Analgésicos no Narcóticos/farmacología , Neoplasias Óseas/fisiopatología , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Tetrazoles/farmacología , Analgésicos no Narcóticos/síntesis química , Animales , Neoplasias Óseas/complicaciones , Carcinoma Ductal de Mama/fisiopatología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Neoplasias Mamarias Animales/fisiopatología , Actividad Motora/efectos de los fármacos , Trasplante de Neoplasias , Dolor/etiología , Dolor/fisiopatología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/fisiología , Antagonistas del Receptor Purinérgico P2X/síntesis química , Piridinas/síntesis química , Ratas Sprague-Dawley , Receptores Purinérgicos P2X7/metabolismo , Tetrazoles/síntesis químicaRESUMEN
BACKGROUND: Deep pain is neglected compared with cutaneous sources. Pressure algometry has been validated in the clinic for assessment of bone-related pain in humans. In animal models of bone-related pain, we have validated the Randall Selitto behavioural test for assessment of acute and pathological bone pain and compared the outcome with more traditional pain-related behaviour measures. METHODS: Randall Selitto pressure algometry was performed over the anteromedial part of the tibia in naïve rats, sham-operated rats, and rats inoculated with MRMT-1 carcinoma cells in the left tibia, and the effect of morphine was investigated. Randall Selitto measures of cancer-induced bone pain were supplemented by von Frey testing, weight-bearing and limb use test. Contribution of cutaneous nociception to Randall Selitto measures were examined by local anaesthesia. RESULTS: Randall Selitto pressure algometry over the tibia resulted in reproducible withdrawal thresholds, which were dose-dependently increased by morphine. Cutaneous nociception did not contribute to Randall Selitto measures. In cancer-bearing animals, compared with sham, significant differences in pain-related behaviours were demonstrated by the Randall Selitto test on day 17 and 21 post-surgery. A difference was also demonstrated by von Frey testing, weight-bearing and limb use tests. CONCLUSION: Our results indicate that pressure applied by the Randall Selitto algometer on a region, where the bone is close to the skin, may offer a way to measure bone-related pain in animal models and could provide a supplement to the traditional behavioural tests and a means to study deep pain.
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Neoplasias Óseas/fisiopatología , Dolor Nociceptivo/diagnóstico , Dimensión del Dolor/métodos , Tibia/fisiopatología , Analgésicos Opioides/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Morfina/farmacología , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Pain is a common and highly debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of multiple mechanisms including both inflammatory and neuropathic processes and also some unique changes. Strong opioids are a mainstay of treatments but side effects are problematic and can compromise optimal pain control. Tapentadol is a novel dual-action drug, both stimulating inhibitory µ-opioid receptors (MOR) and mediating noradrenaline reuptake inhibition (NRI) leading to activation of the inhibitory α-2 adrenoceptor. It has been demonstrated to treat effectively both acute and chronic pain. We here demonstrate the efficacy in a model of cancer-induced bone pain. METHODS: MRMT-1 mammary carcinoma cells were inoculated into the tibia of 6-week-old rats and 2 weeks after, the neuronal responses to a wide range of peripheral stimulation were evaluated. The recordings were made from wide-dynamic range neurons in lamina V of the dorsal horn before and after administration of tapentadol as well as antagonists of the two mechanisms, naloxone or atipamezole. RESULTS: We found marked inhibitions of the neuronal activity with efficacy against mechanical, thermal and electrically evoked activity following tapentadol administration. In addition, the effects of the drug were fully reversible by naloxone and partly by atipamezole, supporting the idea of MOR-NRI dual actions. CONCLUSIONS: These findings add to the mechanistic understanding of cancer-induced bone pain and support the sparse clinical data indicating a possible use of the drug as a therapeutic alternative for cancer patients with metastatic pain complication.
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Neoplasias/complicaciones , Dolor/tratamiento farmacológico , Fenoles/farmacología , Receptores Opioides mu/agonistas , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Analgesia/métodos , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Electrofisiología/métodos , Masculino , Dolor/etiología , Dolor/fisiopatología , Dimensión del Dolor/métodos , Calidad de Vida , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismo , TapentadolRESUMEN
Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1-/- mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1-Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.
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Factores de Intercambio de Guanina Nucleótido/fisiología , Hiperalgesia/etiología , Canales Iónicos/fisiología , Animales , Secuencia de Bases , Células Cultivadas , Factores de Intercambio de Guanina Nucleótido/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Oligodesoxirribonucleótidos , Transducción de SeñalRESUMEN
Neuropathic pain in cancer arises following injury to peripheral or central neurons, in a similar manner to such pain arising from a non-cancer injury. Much of our knowledge of neuropathic pain is based on peripheral originating events with little known about central neuropathic pain. This article explores some of the similarities and differences between cancer and non-cancer-related neuropathic pain. The neural pathways, ion channels, receptors and neurotransmitters that potentially can be altered in both neuropathies are the same; however the nature of the injury, the timing, repeated injuries and the co-existence of simultaneous non-neuropathic pain states lead to potential unique constellations of neuroreceptor and neurotransmitter expression in the context of cancer pain. This in turn may lead to different clinical presentation of pain sensations and potentially lead to specific treatment options.
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Neoplasias/complicaciones , Neuralgia/prevención & control , Analgésicos/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Humanos , Ratones , Trasplante de Neoplasias , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuralgia/etiologíaRESUMEN
The spinal cord is the first relay site in the transmission of nociceptive information from the periphery to the brain. Sensory signals are transmitted from the periphery by primary afferent fibres into the dorsal horn of the spinal cord, where these afferents synapse with intrinsic spinal dorsal horn neurones. Spinal projection neurones then convey this information to higher centres in the brain, where non-noxious and noxious signals can be perceived. During nociceptive transmission, the output of the spinal cord is dependent on various spinal mechanisms which can either increase or decrease the activity of dorsal horn neurones. Such mechanisms include local excitatory and inhibitory interneurones, N-methyl-D-aspartate receptor activation, and descending influences from the brainstem, which can be both inhibitory and excitatory in nature. After nerve injury or conditions of inflammation, shifts can occur in these excitatory and inhibitory mechanisms which modulate spinal excitability, often resulting in the heightened response of dorsal neurones to incoming afferent signals, and increased output to the brain, a phenomenon known as central sensitization. In this review, we consider the ways in which spinal cord activity may be altered in chronic pain states. In addition, we discuss the spinal mechanisms which are targeted by current analgesics used in the management of chronic pain.
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Dolor/fisiopatología , Médula Espinal/fisiopatología , Analgésicos/farmacología , Animales , Tronco Encefálico/fisiopatología , Glutamina/fisiología , Humanos , Vías Nerviosas/fisiopatología , Nociceptores/fisiología , Manejo del Dolor , Células del Asta Posterior/fisiología , Médula Espinal/efectos de los fármacosRESUMEN
Complex networks of pathways project from various structures in the brain to modulate spinal processing of sensory input in a top-down fashion. The rostral ventromedial medulla (RVM) in the brainstem is one major final common output of this endogenous modulatory system and is involved in the relay of sensory information between the spinal cord and brain. The net output of descending neurons that exert inhibitory and facilitatory effects will determine whether neuronal activity in the spinal cord is increased or decreased. By pharmacologically blocking RVM activity with the local anesthetic lignocaine, and then measuring evoked responses of dorsal horn neurons to a range of applied peripheral stimuli, our aim was to determine the prevailing descending influence operating in normal anesthetized animals and animals with experimental neuropathic pain. The injection of 0.8 microl 2% lignocaine into the RVM caused a reduction in deep dorsal horn neuronal responses to electrical and natural stimuli in 64% of normal animals and in 81% of spinal-nerve-ligated (SNL) animals. In normal animals, responses to noxious input were predominantly reduced, while in SNL animals, reductions in spinal cord activity induced by intra-RVM lignocaine further included responses to non-noxious stimuli. This suggests that in terms of activity at least, if not number, descending facilitations are the predominant RVM influence that impacts the spinal cord in normal animals. Moreover, the increase in the proportion of neurons showing a post-lignocaine reduction in dorsal horn activity in SNL rats suggests that the strength of these facilitatory influences increases after neuropathy. This predominant inhibitory spinal effect following the injection of lignocaine into the RVM may be due to blockade of facilitatory On cells.