The saphenous nerve in foot and ankle surgery: its variable anatomy and relevance.

Background: Several studies have raised doubt regarding the role of the saphenous nerve (SN) in the foot, and some authors omit the SN from ankle blocks. Our aim was to assess the SN anatomy with reference to foot and ankle surgery.

Methods: In 29 cadaveric feet the SN was traced to its termination.

An incidence estimation model for multi-stage diseases with differential mortality.

Prevalence and incidence are two important measures of the impact of a disease. For many diseases, incidence is the most useful measure for response planning. However, the longitudinal studies needed to calculate incidence are resource-intensive, so prevalence estimates are often more readily available.

Are drug detection dogs and mass-media campaigns likely to be effective policy responses to psychostimulant use and related harm? Results from an agent-based simulation model.

Background: Agent-based simulation models can be used to explore the impact of policy and practice on drug use and related consequences. In a linked paper (Perez et al., 2011), we described SimAmph, an agent-based simulation model for exploring the use of psychostimulants and related harm amongst young Australians.

SimAmph: an agent-based simulation model for exploring the use of psychostimulants and related harm amongst young Australians.

Background: Computer simulations provide a useful tool for bringing together diverse sources of information in order to increase understanding of the complex aetiology of drug use and related harm, and to inform the development of effective policies. In this paper, we describe SimAmph, an agent-based simulation model for exploring how individual perceptions, peer influences and subcultural settings shape the use of psychostimulants and related harm amongst young Australians.

Methods: We present the conceptual architecture underpinning SimAmph, the assumptions we made in building it, the outcomes of sensitivity analysis of key model parameters and the results obtained when we modelled a baseline scenario.

Estimating incidence of vision-reducing cataract in Africa: a new model with implications for program targets.

Objective: To estimate the incidence of vision-reducing cataract in sub-Saharan Africa and use these data to calculate cataract surgical rates (CSR) needed to eliminate blindness and visual impairment due to cataract.

Methods: Using data from recent population-based, standardized, rapid-assessment surveys, we calculated the age-specific prevalence of cataract (including operated and unoperated eyes) from surveys in 7 "districts" across Africa. This was done at 3 levels of visual acuity.

Evaluating participatory modeling: developing a framework for cross-case analysis.

Participatory modeling is increasingly recognized as an effective way to assist collective decision-making processes in the domain of natural resource management. This article introduces a framework for evaluating projects that have adopted a participatory modeling approach. This evaluation framework--known as the "Protocol of Canberra"--was developed through a collaboration between French and Australian researchers engaged in participatory modeling and evaluation research.

Extending drug ethno-epidemiology using agent-based modelling.

Aims: To show how the inclusion of agent-based modelling improved the integration of ethno-epidemiological data in a study of psychostimulant use and related harms among young Australians.

Methods: Agent-based modelling, ethnographic fieldwork, in-depth interviews and epidemiological surveys.

Setting: Melbourne, Perth and Sydney, Australia.

New horizons in pharmacologic treatment for rheumatic disease pain.

Chronic pain is the major concern for patients with rheumatic diseases, such as low back pain, osteoarthritis, and rheumatoid arthritis, but current therapies are suboptimal. Animal models and emerging clinical data indicate that there is a complex spectrum of neurologic changes, manifesting both nociceptive and neuropathic pain, which are driven by joint pathophysiology and abnormal excitability in peripheral and central pain pathways. A variety of mechanisms and molecular drivers have been identified that can support future segmentation of musculoskeletal pain patients.

Neuropathic pain: emerging treatments.

Neuropathic pain remains one of the most challenging of all neurological diseases and presents a large unmet need for improved therapies. Many mechanistic details are still lacking, but greater knowledge of overlapping mechanisms and disease comorbidities has highlighted key areas for intervention. These include peripheral and central hyperexcitability.

Osteoarthritic pain: a review of current, theoretical and emerging therapeutics.

Background: Despite exciting progress and growth in the understanding of molecular and cellular mechanisms of chronic pain, osteoarthritis (OA) pain remains a challenging clinical entity to treat. There is an emerging diversity of algogenic mechanisms suggesting heterogeneity in pain aetiology in the OA patient population.

Objective/methods: This review article summarises key issues in existing therapies for OA pain and highlights the emerging compounds in early and late development.

Arthritis and pain. Future targets to control osteoarthritis pain.

Clinical presentation of osteoarthritis (OA) is dominated by pain during joint use and at rest. OA pain is caused by aberrant functioning of a pathologically altered nervous system with key mechanistic drivers from peripheral nerves and central pain pathways. This review focuses on symptomatic pain therapy exemplified by molecular targets that alter sensitization and hyperexcitability of the nervous system, for example, opioids and cannabinoids.

Novel molecular targets in pain control.

Purpose Of Review: The complexity of pain processing in clinical pain conditions and in animal models has revealed many time-related changes and an abundance of molecular drug targets. There continues to be insecurity, however, about new target validation in clinical pain and thus most analgesia development is of high risk for evolving new pain therapies. The present review highlights a number of molecular targets being pursued for pain control.

Future pharmacologic management of neuropathic pain.

Neuropathic pain therapy remains enormously challenging despite the increases in knowledge of pain etiology and mechanisms drawn from animal studies. Mechanism-based discovery underlies key approaches toward reduction of peripheral and central hyperexcitability. These include a number of poorly validated molecular targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, as well as downstream regulators of protein phosphorylation.

Novel G protein-coupled receptors as pain targets.

G protein-coupled receptors (GPCRs) and their ligands play a number of important roles in the modulation of acute and chronic pain. Indeed, opioid and cannabinoid ligands are of established therapeutic value for pain management, and further exploitation of the specific GPCR subtypes (delta-opioid, CB1 and CB2) for these ligands may yield more selective, potent analgesics with favorable side effects. More recent identification of a number of other GPCRs involved in pain pathways (eg, sensory neuron specific receptors) and selective ligands that modulate pain transmission, has highlighted further therapeutic opportunities.

A pro-nociceptive role of neuromedin U in adult mice.

Although the neuropeptide neuromedin U (NMU) was first isolated from the spinal cord, its actions in this site are unknown. The recent identification of the NMU receptor subtype 2 (NMU2R) in the spinal cord has increased the interest in investigating the role of NMU in this part of the central nervous system. Here, we report a novel function for NMU in spinal nociception in the mouse.

Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain.

It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF).

Pro-nociceptive effects of neuromedin U in rat.

The neuropeptide neuromedin U (NMU) has been shown to have significant effects on cardiovascular, gastrointestinal and CNS functions. The peptide was first isolated from the porcine spinal cord and later shown to be present in spinal cords of other species. Little is known about the distribution of neuromedin U receptors (NMURs) in the spinal cord and the spinal action of the peptide.

Enhanced thermal antinociceptive potency and anti-allodynic effects of morphine following spinal administration of endotoxin.

Recently, an animal model of central inflammation characterized by widespread cutaneous hyperalgesia and allodynia following intracerebroventricular (i.c.v.

Antisense oligonucleotide knockdown of mGluR1 alleviates hyperalgesia and allodynia associated with chronic inflammation.

Chronic inflammation induced by injection of complete Freund's adjuvant (CFA) into one hindpaw elicits thermal hyperalgesia and mechanical allodynia in the injected paw. Metabotropic glutamate receptors (mGluRs) have been implicated in dorsal horn neuronal nociceptive responses and pain associated with short-term inflammation. The goal of the present study was to assess the role of mGluR1 in the hyperalgesia and allodynia associated with the CFA model of chronic inflammation.

Proenkephalin A gene products activate a new family of sensory neuron--specific GPCRs.

Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities.

Selective depression of nociceptive responses of dorsal horn neurones by SNC 80 in a perfused hindquarter preparation of adult mouse.

Detailed electrophysiological characterisation of spinal opioid receptors in the mouse has been limited due to various technical difficulties. In this study, extracellular single unit recordings were made from dorsal horn neurones in a perfused spinal cord with attached trunk-hindquarter to investigate the role of delta-opioid receptor in mediating nociceptive and non-nociceptive transmission in mouse. Noxious electrical shock, pinch and heat stimuli evoked a mean response of 20.

Spinal delta-opioid receptors mediate suppression of systemic SNC80 on excitability of the flexor reflex in normal and inflamed rat.

Due to low central nervous system (CNS) bioavailability of delta-opioid peptides, little is known about the effect of systemic administration of delta-opioid receptor ligands. The present study examined the effect of non-peptidergic delta-opioid receptor agonists, (+)-4-[(alphaR)-alpha-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) and (-)dibenzoyl-L-tartaric acid salt (SNC86), on the activity of alpha-motoneurons in decerebrate-spinal rats. The flexor reflex was facilitated by C-afferent conditioning inputs, shown by a decrease in mechanical threshold and increase in touch- and pinch-evoked responses.

Knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) alleviates pain and restores opioid efficacy after nerve injury in rats.

1. Nerve injury often produces long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to treatment, being only partially relieved by clinical analgesics, and often insensitive to morphine. With the aim of assessing its therapeutic potential, we examined the effect of antisense oligonucleotide knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) in neuropathic rats.

Neuropeptide FF attenuates allodynia in models of chronic inflammation and neuropathy following intrathecal or intracerebroventricular administration.

Experiments were conducted to explore the effects of Neuropeptide FF acting at spinal and supraspinal sites in models of chronic inflammatory or neuropathic pain and of acute pain. Neuropeptide FF was administered intrathecally (i.t.

Ions in the fire: recent ion-channel research and approaches to pain therapy.

Ion channels form a diverse and sophisticated collection of membrane-bound proteins. They are influenced by many endogenous compounds and physiological stimuli and modulate neuronal activity. It is thus not surprising that they provide attractive targets for the design of novel therapeutics.