Unmet Needs in Pain Therapeutics

Agenda

Tuesday, April 27

Abstracts

Targeting Neuronal and Glial Signalling in Pain Neuroplasticity

Michael W. Salter, Hospital for Sick Children, University of Toronto

Over the past decade a body of evidence has emerged indicating that pain behaviours resulting from injury to peripheral nerves are critically dependent upon interactions between neurons and glia in the dorsal horn of the spinal cord. Microglia have been found to play a causal role in neuropathic pain behaviours resulting from peripheral nerve injury, and specific neuron-microglia-neuron signalling pathways have been elucidated. Within the dorsal horn, microglia suppress neuronal inhibition by a sequence of steps involving activation of microglial P2X4 receptors causing the release of BDNF. BDNF acts on trkB receptors which leads to a rise in intracellular chloride concentration in dorsal horn nociceptive output neurons, transforming the response properties of these neurons. In addition to suppressed inhibition, evidence indicates that following nerve injury there is activity-dependent facilitation at dorsal horn glutamatergic synapses which enhances nociceptive transmission. This enhancement is mediated by intracellular signalling networks involving serine/threonine and tyrosine kinases within nociceptive transmission neurons. Key for this enhancement is facilitation of NMDA receptor function by the non-receptor tyrosine kinase Src. Src is anchored within the NMDA receptor complex by the protein ND2. Disrupting the ND2-Src interaction in vivo attenuates behavioural pain hypersensitivity without the deleterious consequences of directly blocking NMDARs. Thus, understanding of the pathological signalling not only within neurons but also in glial cells, and, as well, the interactions between neurons and glia within the dorsal horn may lead to novel strategies for the management of chronic pain states, strategies not previously expected from a solely neuron-centric view of pain. Supported by the Canadian Institutes of Health Research, the Krembil Foundation and the Howard Hughes Medical Institute.

Inhibitory Mechanisms for Pain Modalities in the Dorsal Horn of the Spinal Cord

Amy MacDermott, Columbia University

The key site in the central nervous system at which pain signaling is transmitted from the periphery, modulated and then projected to higher brain centers is the spinal cord dorsal horn. The most superficial layer of the dorsal horn receives input from small diameter afferent fibers sensitive to noxious heat, cold, mechanical and chemical stimuli. This small region of the central nervous system is predominantly populated by local interneurons. Approximately 30% of these neurons provide local inhibitory control. Working together with descending inhibitory inputs from the brainstem, the inhibitory interneurons in the dorsal horn control the intensity of pain signaling and in some cases, act to prevent non-pain sensory modalities from spilling over into pain pathways. GABA and glycine are the primary inhibitory neurotransmitters released by the inhibitory interneurons. Synaptic release of GABA and glycine transiently activates postsynaptic receptors, suppressing excitability in postsynaptic neurons. Ambient extrasynaptic GABA and glycine can exert a tonic effect on neuronal excitability. Peripheral nerve or spinal cord injury removes this inhibitory control, allowing excitatory drive to become overly strong, contributing to the sensations of hyperalgesia and allodynia. During this presentation, we will be considering the location specificity of inhibition in the dorsal horn and the implications of this specificity for control of excitability related to chronic pain.

Nav1.7 Sodium Channel in Inherited Pain Syndromes

Sulayman D. Dib-Hajj, Yale University School of Medicine

Neuropathic pain is maladaptive and unmet medical need which is associated with hyperexcitability of dorsal root ganglion (DRG) neurons, and is often unresponsive to pharmacotherapy. Transmission of the signal along the pain axis is dependent on voltage-gated sodium channels and first-line drug treatments for neuropathic pain includes non-selective sodium channel blockers. Voltage-gated sodium channel Nav1.7 is preferentially expressed within DRG and sympathetic ganglion neurons, and its gating properties permit amplification of small, slow depolarizations thus acting as a threshold channel. Nav1.7 has recently been shown to underlie inherited human pain syndromes and contributes to pain caused by injury, inflammation and metabolic disorders, making this channel a desirable target for pain treatment. Two sets of autosomal dominant Nav1.7 gain-of-function mutations linked to distinct pain syndromes have recently been identified. Nav1.7 mutations that hyperpolarize activation, slow deactivation, and increase the ramp response to small depolarizations cause Inherited Erythromelalgia (IEM), a disorder characterized by searing, burning pain in distal extremities in response to mild warmth. The characterization of more than ten IEM mutations suggests a correlation of age-of-onset and severity of symptoms with the extent of hyperpolarizing shift in activation of mutant channels. A new Nav1.7 mutation is characterized by different age-of-onset of pain symptoms within the same family, and depolarized fast-inactivation in a splice-isoform-dependent manner. A different set of Nav1.7 mutations that impair fast-inactivation and produce persistent and resurgent currents are associated with Paroxysmal Extreme Pain Disorder (PEPD) characterized by perirectal, perimandibular and periocular pain, triggered by bowel movement and perineal pressure. IEM and PEPD mutations induce hyperexcitability of DRG neurons that express mutant Nav1.7 channels. It is not known why the different types of gain-of-function mutations produce different pain phenotypes. Finally, loss-of-function mutations of Nav1.7 have been identified in patients with congenital insensitivity to pain. Interestingly, while Nav1.7 is normally present within sympathetic ganglion neurons as well as DRG neurons, Nav1.7-related CIP patients do not display autonomic deficits. Studies on Nav1.7-related heritable pain syndromes, and the dynamic regulation of Nav1.7 expression in human painful neuromas and animal models of inflammation and diabetic neuropathy, provide compelling reasons why Nav1.7-specific blockade may provide a new approach for effective treatment of chronic pain.

Fibromyalgia Syndrome: Review of Clinical Presentation, Pathogenesis, Outcome Measures, and Treatment

Daniel J. Clauw, The University of Michigan

Fibromyalgia (FM) is the second most common rheumatic disorder, affecting approximately 2 – 3% of the population. The 1990 American College of Rheumatology criteria require that individuals have a history of chronic widespread pain, and display diffuse tenderness on examination, based on having 11 or greater (or a possible 18) tender points on examination. Alternate diagnostic criteria have been developed that do not require a tender point exam, and instead require both widespread pain and multiple somatic symptoms (e.g. fatigue, memory difficulties, insomnia). Considerable research in the past decade has taught us a great deal about fibromyalgia. It is now clear that this is now one of many “central pain” conditions where the pain and other sensory symptoms are not due to damage or inflammation in peripheral tissues, but instead in part due to augmented processing of pain and sensory information in the central nervous system (CNS). This phenomenon can be identified using experimental pain testing, functional neuroimaging, and analysis of neurotransmitters in the CNS that are involved in pain and sensory transmission. Similarly augmented pain processing (also termed hyperalgesia or allodynia) is also identifiable in the majority of individuals with a variety of other chronic pain states, such as irritable bowel syndrome, idiopathic low back pain, temporomandibular disorder, interstitial cystitis, chronic prostatitis, vulvodynia, and endometriosis. These central pain states: 1) occur approximately 1.5 – 2X as commonly in females than males, 2) have very strong familial and genetic underpinnings, 3) can be triggered by a variety of different stressors, including infection, as well as physical and emotional trauma, and thus deployment to war appears to be a potent trigger of these conditions, 4) respond the same types of pharmacological and non-pharmacological therapies. In fact, even subsets of individuals with “peripheral” pain states such as osteoarthritis will have hyperalgesia/allodynia, and respond to treatments commonly used in the setting of FM, rather than “peripherally based treatments such as NSAIDs, opioids, or procedures. The most effective therapy for FM and related conditions is to employ a patient-centric, multimodal approach that combines the use of pharmacological therapies aimed at improving symptoms, and nonpharmacological therapies aimed at improving function. The non-pharmacological therapies with the highest level of evidence are education, exercise, and cognitive behavioral therapy. The pharmacological therapies with the highest level of evidence include classes or drugs that raise serotonin and norepinephrine (e.g. tricyclics, dual re-uptake inhibitors) and/or drugs that inhibit the release of excitatory neurotransmitters such as Substance P and glutamtate (e.g. pregabalin, gabapentin). One of the primary lessons learned from the study of FM and related conditions is that “central” pain is extremely common in clinical practice, and practitioners need to better understand this type of pain and modify their peripherally-directed (or dualistic) diagnostic and treatment paradigms that assume that pain is either due to inflammation or damage, or due to psychological causes.

Strategies for Developing Effective (& Relevant) Pre-Clinical Models of Pain: Relating Symptoms to Syndromes

Beth A. Winkelstein, University of Pennsylvania

While there is increased basic science work defining specific regulatory pathways of nociception and pain, the development of useful and meaningful pre-clinical models of pain remains an important aspect of developing and implementing effective pain therapeutics and treatment approaches. We combine engineering techniques with behavioral, cellular and molecular assays to develop novel models of injury in the rodent that are relevant to the modes of injury and their pathomechanisms, as well as being clinically-relevant in terms of the symptoms they produce. We use these models to define relationships between tissue insult and injury, local tissue responses, and the widespread cellular mechanisms of nociception, and pain symptoms. This presentation will present this framework for developing pre-clinical models of pain that are useful and relevant. As such, it will summarize findings from integrated clinical studies, in vitro assays, and mechanical experiments that were coordinated to establish several painful models in the rat. This work will be presented with a view towards potential directions for therapeutic interventions and understanding the mechanisms by which pain is initiated and maintained. In particular, relationships between the local tissue environment and the overall systemic responses will be presented to provide a framework for understanding the complete picture of pain and its pathomechanisms. Findings will be presented in the context of diagnosis and treatment to build a foundation for understanding these and other painful disorders. This work has been funded by the CDC, NIH, NSF, NHTSA, DoD, and the Catharine Sharpe Foundation.

Challenges in Discovering New Treatments and Better Models in Pain

Smriti Iyengar, Eli Lilly & Co.

Evolving concepts in pain and the failure of many drug candidates have led to the questioning of current preclinical models of pain. The present talk will attempt to clarify the mechanistic basis and rationale for the use of selected models, relevance of these models to clinical pain, use of these models for drug development, limitations of these models and some newly proposed models.

Emerging Biomarkers and Translational Models for Pain Therapeutic Development

Mark R. Bowlby, Merck Research Laboratories

Biomarkers are defined as quantifiable changes in the expression or state of a protein that correlates with disease severity and response to treatment. Biomarkers have been used for many years in the cardiovascular and oncology fields for determining both treatments and outcomes, but their use in the pain field has only recently gained widespread use. Driven by drug failures and escalating costs in clinical trails, biomarkers have become an important component in the translation of preclinical results into the clinic. Biomarkers are traditionally applied to patients to obtain an objective determination of disease outcome, but in the pain field patient reported outcomes are currently the standard measure of efficacy. Biomarkers, however, are important in pain drug development to demonstrate target engagement and pharmacodynamic activity for a new therapeutic agent, thus providing an empirical link between target and pharmacokinetic data. The use of pharmacodynamic biomarkers and experimental pain models such as capsaicin induced pain and dermal vasodilation, threshold tracking and fMRI will be discussed.

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