Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief

INTRODUCTION: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects. AREAS COVERED: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Nav1.7, 1.8 and 1.9 can cause pain, whilst loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Nav1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Nav1.7 expression. EXPERT OPINION: We believe there is a great future for sodium channel antagonists, particularly Nav1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Nav1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Nav1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant

The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia

BACKGROUND: Trigeminal neuralgia is accompanied by severe mechanical, thermal and chemical hypersensitivity of the orofacial area innervated by neurons of trigeminal ganglion (TG). We examined the role of the voltage-gated sodium channel subtype Nav1.9 in the development of trigeminal neuralgia. RESULTS: We found that Nav1.9 is required for the development of both thermal and mechanical hypersensitivity induced by constriction of the infraorbital nerve (CION). The CION model does not induce change on Nav1.9 mRNA expression in the ipsilateral TG neurons when evaluated 9 days after surgery. CONCLUSIONS: These results demonstrate that Nav1.9 channels play a critical role in the development of orofacial neuropathic pain. New routes for the treatment of orofacial neuropathic pain focussing on regulation of the voltage-gated Nav1.9 sodium channel activity should be investigated

In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP

Mechanistic insights into pain pathways are essential for a rational approach to treating this vast and increasing clinical problem. Sensory neurons that respond to tissue damage (nociceptors) may evoke pain sensations and are typically classified on the basis of action potential velocity. Electrophysiological studies have suggested that most of the C-fiber nociceptors are polymodal, responding to a variety of insults. In contrast, gene deletion studies in the sensory neurons of transgenic mice have frequently resulted in modality-specific deficits. We have used an in vivo imaging approach using the genetically encoded fluorescent calcium indicator GCaMP to study the activity of dorsal root ganglion sensory neurons in live animals challenged with painful stimuli. Using this approach, we can visualize spatially distinct neuronal responses and find that >85% of responsive dorsal root ganglion neurons are modality-specific, responding to either noxious mechanical, cold, or heat stimuli. These observations are mirrored in behavioral studies of transgenic mice. For example, deleting sodium channel Nav1.8 silences mechanical- but not heat-sensing sensory neurons, consistent with behavioral deficits. In contrast, primary cultures of axotomized sensory neurons show high levels of polymodality. After intraplantar treatment with prostaglandin E2, neurons in vivo respond more intensely to noxious thermal and mechanical stimuli, and additional neurons (silent nociceptors) are unmasked. Together, these studies define polymodality as an infrequent feature of nociceptive neurons in normal animals

Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain.

Neuropathic pain patients often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: Oxaliplatin-induced neuropathy, partial sciatic nerve ligation and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large-diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers NaV1.8 and CGRPα. Ablating neurons expressing NaV1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of KV1 voltage-gated potassium channels. Thus silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability

Network orchestration: new role of business incubators?

Purpose – The purpose of this paper is to analyze the performance of incubators in the stages of formationand development of incubated business networks, especially in bottom-up and top-down network models.Design/methodology/approach – The research is defined as qualitative and descriptive, with theapplication of multiple case studies, in which two networks of incubated businesses were investigated, onebeing top-down and the other bottom-up, which emerged within the incubation process of two businessincubators (CIETEC and INCIT). To make the study operational, 11 semi-structured interviews were carriedout and the thematic analysis of content was developed.Findings – The results pointed out that in the top-down network the incubator performs a new assignment,the network orchestration, which corresponds to the actions of formation, coordination and governance of thegroup. In the bottom-up network, it was found that the role of the incubator was to expand the value offersusually practiced.Research limitations/implications – As a limitation of the research, the very limitation of case studiesis pointed out that is they do not allow for generalizations.Practical implications – The research contributes to reflections on the effectiveness of the incubator andsheds light on the complementarity of networks in incubation processes, providing gains for incubators,incubated businesses and society.Originality/value – The originality of this document is the new role of the incubator, which isorchestration, and its categorization. The results allow us to understand the effects of providing networks andrelationships for incubated businesses. In addition, this study broadens the focus of traditional analyses of theincubator–incubated duo to consider the incubator–network–incubated trio

Governance and Social Network: Analysis in Cooperatives of Small Citrus Producers in the São Paulo State, Brazil

The purpose of this paper is to investigate if the network governance structure adopted by small producers’ citrus cooperatives has allowed the reduction of risks in transactions, ex-ante (adverse selection) and ex-post (moral hazard), and the problems of opportunism downstream and upstream of the production chain. The planned methodological procedure included the structuring and research of two case studies in cooperatives of small orange producers in the interior of the state of São Paulo, Brazil, comprising a sample of 35 cooperative members surveyed between the two cooperatives analyzed. The analyzes were supported by the Transaction Cost Economics and Social Network approaches. Results indicate the importance of the cooperatives and their network format, as economic agents, in maintaining small producers in the citrus industry activity, allowing the reduction of risks in transactions and the problems of opportunism, downstream and upstream of the chain. It was verified the academic contribution and theoretical reinforcement brought by this study - through the empirical surveys and results produced - to the theory of hybrid governance formats, which lacks empirical support and greater analytical strengthening on the part of the academy, according to its own authors. It is suggested, for future analysis, the use of the network governance approach aimed at strengthening the class of small producers of other agribusiness cultures, also using the theoretical basis belonging to NIE, TCE and Networks. The continuity of analyzes based on relational governance, with institutional and transactional economics as a basis, represents not only academic documentation and support for small rural producers of different cultures, but also the guarantee of theoretical robustness to a structure that is still incipient in historical terms, which finds in Brazilian agribusiness a fertile ground for its development and materialization

VIBRIO FISCHERI: Uma abordagem prática através da Biotecnologia

Vibrio fischeri é uma bactéria marinha luminescente e é utilizada em ensaios de detecção de compostos tóxicos que possam estar presentes em águas e efluentes. A luminescência está ligada ao metabolismo bacteriano,que é sensível à ação de substâncias tóxicas, há redução na emissão de luz. Quanto mais tóxica for a amostra, maiora perda de luminescência. Essa redução é rapidamente desencadeada, assim, Vibrio fischeri é utilizada em avaliações prévias para identificação de toxicidade em amostras ambientais, de extrema importância para o diagnóstico de toxicidade em estações de tratamento de efluentes e em acidentes ambientais

O HIPOTÁLAMO DORSOMEDIAL E A ORGANIZAÇÃO DA RESPOSTA CARDIOVASCULAR AO ESTRESSE EMOCIONAL: UMA PERSPECTIVA FUNCIONAL

Emotional stress results in activation of specific pathways into central nervous system, which produces autonomic, behavioral and endocrine responses. It is known that repetitive or continuous exposition to stress situations may result in various pathologic states, for example, arterial hypertension. Classically, the hypothalamus plays an essential role in the integration of physiological responses to emotional stress. Recent studies demonstrate that a specific nucleus from hypothalamus, the dorsomedial hypothalamus (DMH), is an essential component of central pathways that mediate the cardiovascular response to emotional stress. Inhibition of neurons in this area reduces the increases in heart rate and blood pressure in rats submitted to emotional stress paradigms. Conversely, pharmacological activation of DMH neurons evokes increases on heart rate, blood pressure, adrenocorticotrophic hormone, locomotor activity and sympathetic activity. The similarity of this response with that produced during emotional stress suggests that this area is crucial in the integration of the physiological responses to emotional stress. The present review will discuss the central pathways used by DMH in the organization of the cardiovascular response to emotional stress.O estresse emocional resulta em ativação de vias específicas do sistema nervoso central, que produzem respostas autonômicas, comportamentais e endócrinas. Sabe-se que situações de estresse recorrentes ou prolongadas podem resultar em vários estados patológicos, como por exemplo, a hipertensão arterial. O Hipotálamo tem papel fundamental na integração das respostas fisiológicas ao estresse emocional. Particularmente, estudos têm mostrado que um núcleo específico do hipotálamo, o hipotálamo dorsomedial (DMH), é um componente fundamental das vias centrais mediadoras das respostas cardiovasculares ao estresse emocional. A inibição dos neurônios dessa área reduz os aumentos de freqüência cardíaca e de pressão arterial em ratos quando submetidos à situações de estresse emocional. Ao contrário, a ativação farmacológica dos neurônios do DMH produz aumento na frequência cardíaca, pressão arterial, hormônio adrenocorticotrópico (ACTH), atividade locomotora e na atividade simpática para diversos leitos vasculares. A similaridade dessa resposta com aquela produzida durante a situação real de estresse emocional sugere que esta área é fundamental na integração da resposta fisiológica ao estresse. A presente revisão tem como objetivo mostrar, através de resultados de estudos recentes, as vias centrais utilizadas pelo DMH na organização da resposta cardiovascular ao estresse emocional

Sensory neuron–derived NaV1.7 contributes to dorsal horn neuron excitability

Expression of the voltage-gated sodium channel NaV1.7 in sensory neurons is required for pain sensation. We examined the role of NaV1.7 in the dorsal horn of the spinal cord using an epitope-tagged NaV1.7 knock-in mouse. Immuno–electron microscopy showed the presence of NaV1.7 in dendrites of superficial dorsal horn neurons, despite the absence of mRNA. Rhizotomy of L5 afferent nerves lowered the levels of NaV1.7 in the dorsal horn. Peripheral nervous system–specific NaV1.7 null mutant mice showed central deficits, with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. NaV1.7 blocker PF05089771 diminished excitability in dorsal horn neurons but had no effect on NaV1.7 null mutant mice. These data demonstrate an unsuspected functional role of primary afferent neuron-generated NaV1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis