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Elucidating Pain Mechanism with Venom-Derived Peptides and Natural Toxins: What Doesn’t Kill You Might Treat Your Pain

Pain following envenomation is a well-known phenomenon: touching a nettle, stepping on a bee or becoming wrapped in jellyfish tentacles are relatively common encounters in our lives, and all of these have in common the memorable, and at times severe, pain that results. Indeed, pain-causing venoms and toxins have evolved on numerous occasions in many species across the animal and plant kingdoms, in particular for defensive or deterrent purposes – how else might a small insect like a bee impact a goliath like a human otherwise? Without doubt, inflicting pain is both an intuitive and evolutionarily validated strategy ensuring the survival of venomous animals, and for this reason, a plethora of venom peptides and toxins target sensory neurons. However, venom- and toxin-induced pain does not merely serve as a tool to teach us about avoidance. The at times unparalleled potency and selectivity of venom-derived peptides and natural toxins for the molecular machinery involved in the processes of signal transduction and transmission make these compounds ideally suited to unravel the mechanisms of pain. These insights in turn can be used to identify novel pain targets, or to develop potent and selective analgesic candidates.

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Novel Synaptic Mechanisms for Chronic Pain and Anxiety

Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli ‘teach’ humans and animals to avoid potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time.  Conventional pain medicines often fail to control chronic pain.  Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain.  We have characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Our results demonstrate that cortical LTPs contribute to chronic pain and anxiety; and inhibiting these different forms of LTP may help us to develop novel drugs for the future treatment of chronic pain and anxiety.

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Modeling Emotional Pain in an Animal Model of Neuropathic Pain

Often, the focus in animal models of chronic pain is on the experience of pain. However, in humans, co-morbidity with depressive symptoms is highly common. We modelled this in rats using the sciatic nerve ligation (SNL) model of chronic neuropathic pain. The level of neuropathic pain was assessment by von Frey hairs and demonstrated clear mechanical allodynia. We tested a battery of behavioral tests to examine comorbid emotional symptoms, which identified large individual variability, with some animals presenting only symptoms of mechanical allodynia (emotionally-unaffected), but others exhibiting also comorbid emotional symptoms (emotionally-affected). Both groups displayed similar levels of mechanical allodynia. Preventing the degradation of endogenous cannabinoids by inhibiting fatty acid amide hydrolase (FAAH) did not reduce mechanical allodynia, but significantly reduced emotional symptoms exclusively in emotionally-affected individuals.
In aggregate, this shows that the mechanisms involved in the emotional symptoms differ from underlying neuropathic pain per se. Enhancing endocannabinoid modulation may be beneficial for the emotional symptoms co-morbidity, even if not reducing the chronic pain per se. This could already contribute significantly to the well-being of patients suffering from chronic pain.

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Dysregulated Pain Processing and Pain Plasticity in Patients with Major Depressive Disorder

We studied pain processing in patients with major depressive disorder (MDD) on several levels to understand whether the depressive condition amplifies pain experience and/or pain plasticity. Quantitative sensory testing revealed that MDD patients exhibited only liminal differences of their somatosensory pattern compared to healthy subjects. In contrast, when challenged by two different experimental models of hyperalgesia human pain-LTP or sustained painful heat exposure) MDD patients responded with similar heat hyperalgesia, but significantly enhanced secondary hyperalgesia and allodynia pointing towards increased central sensitization, which correlated to their degree of anxiety and depression. Importantly, SNRIs mitigated the hyperalgesia dose-dependently to a very relevant degree.

Moreover, as tested by conditioning pain modulation, descending pain control shifted significantly towards facilitation in MDD patients. Imaging experiments revealed significantly lower functional connectivity and a complete absence of adaptive engagement of prefrontal cortical areas during the hyperalgesia-inducing sustained heat stimulation. Collectively, the data support the interpretation that MDD patients are prone to respond with exaggerated pain amplification related to an imbalance of their inhibitory vs. facilitatory descending pain control, which may be related to their deficit of prefrontal pain control.

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Demystifying Mechanisms of Placebo Effects Across the Lifespan

The placebo effect is one of the most striking and well-known demonstrations of the mind’s influence on the experience of pain. While for decades clinical trials have aimed to reduce the placebo effect, there is growing interest in leveraging the placebo effect to improve pain treatments and to relieve suffering. This includes moving beyond a narrow understanding of the placebo effect as expectations for a placebo pill, and instead moving towards an understanding that the brain’s ‘inner pharmacy’ can be leveraged in a variety of ways through clinical care. To effectively leverage these placebo effects in clinical care, it is essential to understand their psychological and neurobiological mechanisms. In this Panel Workshop, our three speakers will share cutting-edge findings that demonstrate how placebo effects operate through a variety of mechanisms including conditioning effects, social learning, and via ‘mindsets’ about the body and its capacity to heal. Our speakers will also highlight how placebo effects may change with age, sharing novel data from child and adult samples. Finally, our speakers will discuss why demystifying placebo mechanisms is critical to effectively and ethically leveraging placebo effects in clinical care across the lifespan.

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Leveraging Mindsets to Ethically Harness the Placebo Effect in Adults and Youth

Dr. Lauren Heathcote will argue that the power of the placebo does not reside in the sham treatment itself; rather, it comes from the psychosocial forces that surround the patient and the treatment. To that end, she will share new data suggesting that ‘mindsets’ are key mechanisms involved in the placebo effect in both adults and in youth. In a series of new cross-sectional studies, she will show that mindsets about the body and its capacity to heal are uniquely associated with pain outcomes in over 200 children and adults with chronic pain as well as childhood cancer survivors. She will also share the findings of a new experimental study with 800 adults receiving the covid vaccine, in which a brief body mindset intervention changed the report and experience of aches and pains and other flu-like symptoms; this mindset intervention is now being applied to youth undergoing painful surgical procedures.  

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Age, Sex and Race Effects on Placebo Analgesia: Results from a Large Cohort Study in Chronic Pain and Healthy Participants

This talk will present recent results with sex, race, and age being explored in a large cross-sectional study enrolling over 800 chronic pain patients and matched controls. Colloca and her team were the first to demonstrate influences of race/ethnicity on placebo hypoalgesia. Racial effects on placebo hypoalgesia are small and negligible. AfroAmerican/Black participants have lower placebo effects which are mediated by conditioning strength. Concordance between the experimenter and participant race induced greater placebo hypoalgesia in chronic pain patients hinting to the fact that disparities and racial biases may play a role. Independently of gonadal hormone levels, women show stronger placebo effects than men. There were also statistically significant sex differences for the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related larger placebo effects in women. Finally, distinct adulthood ages contribute to larger placebo effects in chronic pain patients with placebo effects (unpublished data). Overall, these findings are new, informative for clinical practice and trials and new age-related research approaches.

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Pain, Placebo, and Positive Feedback Loops

Dr. Tor Wager will share how social influence and conditioned cue effects act as key mechanisms driving placebo effects in adults, and how these could be ethically leveraged to enhance placebo effects in clinical care.  He will argue that these mechanisms can create the conditions for positive feedback loops between beliefs and the experience of pain and other symptoms. Targeting these feedback loops can result in effective psychological treatments for chronic pain.  

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Novel Peripheral Mechanisms of Neuro-immune Crosstalk in Chronic Pain

This workshop will elucidate novel mechanisms whereby non-neuronal cells in peripheral tissues drive neuroinflammation and chronic pain. New data will be presented that reveal important roles for keratinocytes, adipocytes (fat cells), muscle macrophages, and B cells in the onset and maintenance of different types of chronic pain. In the first presentation, Dr. Matthieu Talagas will describe physical and functional connections between epidermal keratinocytes and nociceptive sensory neurons essential for the transduction of nociceptive input. In the second presentation, Dr. Andrea Nackley will describe how catecholamine activation of adipocyte Adrb3 leads to immune remodeling, enhanced nociceptor activity, and central sensitization in a mouse model of chronic overlapping pain conditions (COPCs). In the third presentation, Dr. Kathleen Sluka will describe key muscle-immune-neuro interactions that lead to hyperalgesia in response to an acute bout of physical activity and those that lead to analgesia in a mouse model of widespread musculoskeletal pain. In the fourth presentation, Dr. Peter Grace will describe how injury-induced B cell differentiation in lymphoid organs results in formation of (auto)antibody-antigen complexes that drive neuropathic pain. Upon completion of this session, attendees will be able to 1) define unique mechanisms whereby peripheral keratinocytes, adipocytes, muscles, and immune cells drive nociception and pain, 2) describe how these mechanisms are modified by genetic (eg, sex) and/or environmental (eg, stress) factors, and 3) recognize the potential utility of peripherally-targeted treatments for chronic pain.

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The Role of Adipocytes in Chronic Pain and Inflammation

The origin of chronic overlapping pain conditions (COPCs), such as temporomandibular disorder and fibromyalgia, is linked to enhanced catecholaminergic tone. In earlier work, we provided the first demonstration that catecholamines promote chronic multi-site pain through activation of adrenergic receptor beta-3 (Adrb3). Here, new data will be presented in a clinically-relevant mouse model of COPCs that reveal Adrb3 mediates chronic multi-site pain through its location on peripheral adipocytes (fat cells). Activation of adipocyte Adrb3 leads to stimulation of pro-inflammatory cytokines and enhanced activity of primary afferent nociceptors. The resulting pain is then maintained by neuroplastic changes in the central nervous system that are characterized by increased production of pro-inflammatory cytokines, phosphorylation of mitogen-activated protein kinases (MAPKs), and increased activation of glia and nociceptors.

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