Handbook of experimental pharmacology
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It is evident that chronic pain can modify the excitability of central nervous system which imposes a specific challenge for the management and for the development of new analgesics. The central manifestations can be difficult to quantify using standard clinical examination procedures, but quantitative sensory testing (QST) may help to quantify the degree and extend of the central reorganization and effect of pharmacological interventions. Furthermore, QST may help in optimizing the development programs for new drugs. ⋯ As most of the drug development programs in the area of pain management have not been very successful, the pharmaceutical industry has started to utilize the complementary knowledge obtained from QST profiling. Linking patients QST profile with drug efficacy profile may provide the fundamentals for developing individualized, targeted pain management programs in the future. Linking QST-assessed pain mechanisms with treatment outcome provides new valuable information in drug development and for optimizing the management regimes for chronic pain.
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Human and mouse genetic studies have led to significant advances in our understanding of the role of voltage-gated sodium channels in pain pathways. In this chapter, we focus on Nav1.7, Nav1.8, Nav1.9 and Nav1.3 and describe the insights gained from the detailed analyses of global and conditional transgenic Nav knockout mice in terms of pain behaviour. The spectrum of human disorders caused by mutations in these channels is also outlined, concluding with a summary of recent progress in the development of selective Nav1.7 inhibitors for the treatment of pain.
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Pain and itch are generally regarded antagonistic as painful stimuli such as scratching suppresses itch. Moreover, inhibition of pain processing by opioids generates itch further supporting their opposing role. Separate specific pathways for itch and pain processing have been uncovered, and several molecular markers have been established in mice that identify neurons involved in the processing of histaminergic and non-histaminergic itch on primary afferent and spinal level. ⋯ Rather than separating itch and pain, research concepts should therefore address the common mechanisms. Such an approach appears most appropriate for clinical conditions of neuropathic itch and pain and also chronic inflammatory conditions. While itch researchers can benefit from the large body of information of the pain field, pain researchers will find behavioral readouts of spontaneous itch much simpler than those for spontaneous pain in animals and the skin as source of the pruritic activity much more accessible even in patients.
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Inhibitory interneurons, which use GABA and/or glycine as their principal transmitter, have numerous roles in regulating the transmission of sensory information through the spinal dorsal horn. These roles are likely to be performed by different populations of interneurons, each with specific locations in the synaptic circuitry of the region. ⋯ Several mechanisms have been proposed for this disinhibition, including death of inhibitory interneurons, decreased transmitter release, diminished activity of these cells and reduced effectiveness of GABA and glycine as inhibitory transmitters. However, despite numerous studies on this important topic, it is still not clear which (if any) of these mechanisms contributes to neuropathic pain after nerve injury.
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The antiepileptic potential of Cannabis sativa preparations has been historically recognized. Recent changes in legal restrictions and new well-documented cases reporting remarkably strong beneficial effects have triggered an upsurge in exploiting medical marijuana in patients with refractory epilepsy. Parallel research efforts in the last decade have uncovered the fundamental role of the endogenous cannabinoid system in controlling neuronal network excitability raising hopes for cannabinoid-based therapeutic approaches. ⋯ To support translation from anecdote-based practice to evidence-based therapy, the present review first introduces current preclinical and clinical efforts for cannabinoid- or endocannabinoid-based epilepsy treatments. Next, recent advances in our knowledge of how endocannabinoid signaling limits abnormal network activity as a central component of the synaptic circuit-breaker system will be reviewed to provide a framework for the underlying neurobiological mechanisms of the beneficial and adverse effects. Finally, accumulating evidence demonstrating robust synapse-specific pathophysiological plasticity of endocannabinoid signaling in epileptic networks will be summarized to gain better understanding of how and when pharmacological interventions may have therapeutic relevance.