Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method.

Involving research users in setting priorities for research is essential to ensure the outcomes are patient-centred and maximise its value and impact. The Musculoskeletal Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across musculoskeletal disorders. The Child Health and Nutrition Research Initiative (CHNRI) method of setting research priorities with a range of stakeholders was used, involving four stages and two surveys, to: (1) gather research uncertainties, (2) consolidate these, (3) score uncertainties against importance and impact, and (4) analyse scoring for prioritisation. 213 people responded to the first survey and 285 people to the second, representing clinicians, researchers, and people with musculoskeletal disorders. Key priorities included developing and testing new treatments, better treatment targeting, early diagnosis, prevention, and better understanding and management of pain, with an emphasis on understanding underpinning mechanisms. We present a call to action to researchers and funders to target these priorities.

The pharmacology of voltage-gated sodium channels in sensory neurones.

Voltage-gated sodium channels (VGSCs) are vital for the normal functioning of most excitable cells. At least nine distinct functional subtypes of VGSCs are recognized, corresponding to nine genes for their pore-forming alpha-subunits. These have different developmental expression patterns, different tissue distributions in the adult and are differentially regulated at the cellular level by receptor-coupled cell signalling systems. Unsurprisingly, VGSC blockers are found to be useful as drugs in diverse clinical applications where excessive excitability of tissue leads to pathological dysfunction, e.g. epilepsy or cardiac tachyarrhythmias. The effects of most clinically useful VGSC blockers are use-dependent, i.e. their efficacy depends on channel activity. In addition, many natural toxins have been discovered that interact with VGSCs in complex ways and they have been used as experimental probes to study the structure and function of the channels and to better understand how drugs interact with the channels. Here we have attempted to summarize the properties of VGSCs in sensory neurones, discuss how they are regulated by cell signalling systems and we have considered briefly current concepts of their physiological function. We discuss in detail how drugs and toxins interact with archetypal VGSCs and where possible consider how they act on VGSCs in peripheral sensory neurones. Increasingly, drugs that block VGSCs are being used as systemic analgesic agents in chronic pain syndromes, but the full potential for VGSC blockers in this indication is yet to be realized and other applications in sensory dysfunction are also possible. Drugs targeting VGSC subtypes in sensory neurones are likely to provide novel systemic analgesics that are tissue-specific and perhaps even disease-specific, providing much-needed novel therapeutic approaches for the relief of chronic pain.

Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices of GABAB1 receptor subunit knockout mice.

The recently developed GABAB1 receptor subunit knockout (GABAB1 -/-) mouse displays complete loss of GABAB receptor function and develops complex generalized epilepsies including absence type, audiogenic as well as spontaneous generalized seizures with electrographic spike-wave discharge signatures. To gain insight into the cellular mechanisms contributing to the generation and maintenance of this epileptic phenotype we have compared epileptiform activity induced in hippocampal slices obtained from GABAB1 -/- and wild type (GABAB1 +/+) littermates. Deletion of the GABAB1 receptor subunit had no effect on a range of passive membrane properties of CA3 pyramidale neurones, non-synaptic epileptiform field bursting and spreading depression recorded in 6mM K+/Ca2+-free medium, and inter-ictal synaptically-induced epileptiform activity induced by 100 microM 4-aminopyridine (4-AP). In contrast, synaptic epileptiform activity induced by 10 microM bicuculline, removal of extracellular Mg2+ or addition of 10 microM oxotremorine was enhanced in GABAB1 -/- slices. Acute blockade of GABAB receptors using a selective antagonist only partly mimicked these effects. It is suggested that the exaggerated in vitro epileptiform activity is caused by both acute and chronic consequences of the loss of GABAB receptor function in vivo. Specifically, enhancement of N-methyl-d-aspartate (NMDA) receptor triggered synaptic processes, arising from the loss of the GABAB receptor-mediated inhibitory postsynaptic potential (IPSP, together with a possible promotion of depolarising IPSPs due to the removal of GABAB autoreceptor function) is likely to underlie these effects.