SSFN Webinar - Pain research
Neuromodulation of subjective experience
Many psychoactive substances are used with the aim of altering experience, e.g. as analgesics, antidepressants or antipsychotics. These drugs act on specific receptor systems in the brain, including the opioid, serotonergic and dopaminergic systems. In this talk, I will summarise human drug studies targeting opioid receptors and their role for human experience, with focus on the experience of pain, stress, mood, and social connection. Opioids are only indicated for analgesia, due to their potential to cause addiction. When these regulations occurred, other known effects were relegated to side effects. This may be the cause of the prevalent myth that opioids are the most potent painkillers, despite evidence from head-to-head trials, Cochrane reviews and network meta-analyses that opioids are not superior to non-opioid analgesics in the treatment of acute or chronic non-cancer pain. However, due to the variability and diversity of opioid effects across contexts and experiences, some people under some circumstances may indeed benefit from prolonged treatment. I will present data on individual differences in opioid effects due to participant sex and stress induction. Understanding the effects of these commonly used medications on other aspects of the human experience is important to ensure correct use and to prevent unnecessary pain and addiction risk.
Protocols for the social transfer of pain and analgesia in mice
We provide protocols for the social transfer of pain and analgesia in mice. We describe the steps to induce pain or analgesia (pain relief) in bystander mice with a 1-h social interaction with a partner injected with CFA (complete Freund’s adjuvant) or CFA and morphine, respectively. We detail behavioral tests to assess pain or analgesia in the untreated bystander mice. This protocol has been validated in mice and rats and can be used for investigating mechanisms of empathy. Highlights • A protocol for the rapid social transfer of pain in rodents • Detailed requirements for handling and housing conditions • Procedures for habituation, social interaction, and pain induction and assessment • Adaptable for social transfer of analgesia and may be used to study empathy in rodents https://doi.org/10.1016/j.xpro.2022.101756
NEW TREATMENTS FOR PAIN: Unmet needs and how to meet them
“Of pain you could wish only one thing: that it should stop. Nothing in the world was so bad as physical pain. In the face of pain there are no heroes.- George Orwell, ‘1984’ " "Neuroscience has revealed the secrets of the brain and nervous system to an extent that was beyond the realm of imagination just 10-20 years ago, let alone in 1949 when Orwell wrote his prophetic novel. Understanding pain, however, presents a unique challenge to academia, industry and medicine, being both a measurable physiological process as well as deeply personal and subjective. Given the millions of people who suffer from pain every day, wishing only, “that it should stop”, the need to find more effective treatments cannot be understated." "‘New treatments for pain’ will bring together approximately 120 people from the commercial, academic, and not-for-profit sectors to share current knowledge, identify future directions, and enable collaboration, providing delegates with meaningful and practical ways to accelerate their own work into developing treatments for pain.
Visualization and manipulation of our perception and imagery by BCI
We have been developing Brain-Computer Interface (BCI) using electrocorticography (ECoG) [1] , which is recorded by electrodes implanted on brain surface, and magnetoencephalography (MEG) [2] , which records the cortical activities non-invasively, for the clinical applications. The invasive BCI using ECoG has been applied for severely paralyzed patient to restore the communication and motor function. The non-invasive BCI using MEG has been applied as a neurofeedback tool to modulate some pathological neural activities to treat some neuropsychiatric disorders. Although these techniques have been developed for clinical application, BCI is also an important tool to investigate neural function. For example, motor BCI records some neural activities in a part of the motor cortex to generate some movements of external devices. Although our motor system consists of complex system including motor cortex, basal ganglia, cerebellum, spinal cord and muscles, the BCI affords us to simplify the motor system with exactly known inputs, outputs and the relation of them. We can investigate the motor system by manipulating the parameters in BCI system. Recently, we are developing some BCIs to visualize and manipulate our perception and mental imagery. Although these BCI has been developed for clinical application, the BCI will be useful to understand our neural system to generate the perception and imagery. In this talk, I will introduce our study of phantom limb pain [3] , that is controlled by MEG-BCI, and the development of a communication BCI using ECoG [4] , that enable the subject to visualize the contents of their mental imagery. And I would like to discuss how much we can control our cortical activities that represent our perception and mental imagery. These examples demonstrate that BCI is a promising tool to visualize and manipulate the perception and imagery and to understand our consciousness. References 1. Yanagisawa, T., Hirata, M., Saitoh, Y., Kishima, H., Matsushita, K., Goto, T., Fukuma, R., Yokoi, H., Kamitani, Y., and Yoshimine, T. (2012). Electrocorticographic control of a prosthetic arm in paralyzed patients. AnnNeurol 71, 353-361. 2. Yanagisawa, T., Fukuma, R., Seymour, B., Hosomi, K., Kishima, H., Shimizu, T., Yokoi, H., Hirata, M., Yoshimine, T., Kamitani, Y., et al. (2016). Induced sensorimotor brain plasticity controls pain in phantom limb patients. Nature communications 7, 13209. 3. Yanagisawa, T., Fukuma, R., Seymour, B., Tanaka, M., Hosomi, K., Yamashita, O., Kishima, H., Kamitani, Y., and Saitoh, Y. (2020). BCI training to move a virtual hand reduces phantom limb pain: A randomized crossover trial. Neurology 95, e417-e426. 4. Ryohei Fukuma, Takufumi Yanagisawa, Shinji Nishimoto, Hidenori Sugano, Kentaro Tamura, Shota Yamamoto, Yasushi Iimura, Yuya Fujita, Satoru Oshino, Naoki Tani, Naoko Koide-Majima, Yukiyasu Kamitani, Haruhiko Kishima (2022). Voluntary control of semantic neural representations by imagery with conflicting visual stimulation. arXiv arXiv:2112.01223.
Selectively Silencing Nociceptor Sensory Neurons
Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.
Keeping axons alive after injury: Inhibiting programmed axon death
Activation of pro-degenerative protein SARM1 in response to diverse physical and disease-relevant injuries triggers programmed axon death. Original studies indicated substantially decreased levels of SARM1 were required for neuroprotection. However, we demonstrate that lowering SARM1 levels by 50% in Sarm1 haploinsufficient mice delays axon degeneration in vivo (after sciatic nerve transection), in vitro (in response to diverse traumatic, neurotoxic, and genetic triggers), and partially prevents neurite outgrowth defects in mice lacking pro-survival factor NMNAT2. We also demonstrate the capacity for Sarm1 antisense oligonucleotides to decrease SARM1 levels by more than 50% which delays or prevents programmed axon degeneration in vitro. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injuries. These data demonstrate that axon protection occurs in a Sarm1 gene-dose responsive manner and that SARM1 lowering agents have therapeutic potential. Thus, antisense oligonucleotide targeting of Sarm1 is a promising therapeutic strategy against diverse triggers of axon degeneration.
Selectively Silencing Nociceptor Sensory Neurons
Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.
Bedside to bench and back again, a path to translational pain research?
Pain has both a sensory and emotional component and is driven by activation of sensory neurones called nociceptors that are tuned to detect noxious stimuli in a process called nociception. Although nociception functions as a detect and protect mechanism. and is found in many organisms, this system becomes dysregulated in a number of conditions where chronic pain presents as a key symptom, for example osteoarthritis. Nociceptors do not innervate empty space though and do not act alone. Going beyond the neurone, other cell types, such as fibroblast-like synoviocytes interact with and modify the function of nociceptors, which is likely a key contributor to the chronification of pain. In this talk, I will look at how combining pre-clinical mouse work with human tissue and genetics might provide a way to accelerate new analgesics from bench to bedside, giving examples from our work in joint pain, bowel pain and labour pain.
Learning in pain: probabilistic inference and (mal)adaptive control
Pain is a major clinical problem affecting 1 in 5 people in the world. There are unresolved questions that urgently require answers to treat pain effectively, a crucial one being how the feeling of pain arises from brain activity. Computational models of pain consider how the brain processes noxious information and allow mapping neural circuits and networks to cognition and behaviour. To date, they have generally have assumed two largely independent processes: perceptual and/or predictive inference, typically modelled as an approximate Bayesian process, and action control, typically modelled as a reinforcement learning process. However, inference and control are intertwined in complex ways, challenging the clarity of this distinction. I will discuss how they may comprise a parallel hierarchical architecture that combines pain inference, information-seeking, and adaptive value-based control. Finally, I will discuss whether and how these learning processes might contribute to chronic pain.
Anterior Cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia
Empathy plays a critical role in social interactions, and many species, including rodents, display evolutionarily conserved behavioral antecedents of empathy. In both humans and rodents, the anterior cingulate cortex (ACC) encodes information about the affective state of others. However, little is known about which downstream targets of the ACC contribute to empathy behaviors. We optimized a protocol for the social transfer of pain behavior in mice and compared the ACC-dependent neural circuitry responsible for this behavior with the neural circuitry required for the social transfer of two related states: analgesia and fear. We found that a 1-hour social interaction between a bystander mouse and a cagemate experiencing inflammatory pain led to congruent mechanical hyperalgesia in the bystander. This social transfer led to activation of neurons in the ACC and several downstream targets, including the nucleus accumbens (NAc), which was revealed by monosynaptic rabies virus tracing to be directly connected to the ACC. Bidirectional manipulation of activity in ACC-to-NAc inputs influenced the acquisition of socially transferred pain. Further, the social transfer of analgesia also depended upon ACC-NAc inputs. By contrast, the social transfer of fear instead required activity in ACC projections to the basolateral amygdala. This shows that mice rapidly adopt the sensory-affective state of a social partner, regardless of the valance of the information (pain, fear, or pain relief). We find that the ACC generates specific and appropriate empathic behavioral responses through distinct downstream targets. More sophisticated understanding of evolutionarily conserved brain mechanisms of empathy will also expedite the development of new therapies for the empathy-related deficits associated with a broad range of neuropsychiatric disorders.
Life of Pain and Pleasure
The ability to experience pain is old in evolutionary terms. It is an experience shared across species. Acute pain is the body’s alarm system, and as such it is a good thing. Pain that persists beyond normal tissue healing time (3-4 months) is defined as chronic – it is the system gone wrong and it is not a good thing. Chronic pain has recently been classified as both a symptom and disease in its own right. It is one of the largest medical health problems worldwide with one in five adults diagnosed with the condition. The brain is key to the experience of pain and pain relief. This is the place where pain emerges as a perception. So, relating specific brain measures using advanced neuroimaging to the change patients describe in their pain perception induced by peripheral or central sensitization (i.e. amplification), psychological or pharmacological mechanisms has tremendous value. Identifying where amplification or attenuation processes occur along the journey from injury to the brain (i.e. peripheral nerves, spinal cord, brainstem and brain) for an individual and relating these neural mechanisms to specific pain experiences, measures of pain relief, persistence of pain states, degree of injury and the subject's underlying genetics, has neuroscientific and potential diagnostic relevance. This is what neuroimaging has afforded – a better understanding and explanation of why someone’s pain is the way it is. We can go ‘behind the scenes’ of the subjective report to find out what key changes and mechanisms make up an individual’s particular pain experience. A key area of development has been pharmacological imaging where objective evidence of drugs reaching the target and working can be obtained. We even now understand the mechanisms of placebo analgesia – a powerful phenomenon known about for millennia. More recently, researchers have been investigating through brain imaging whether there is a pre-disposing vulnerability in brain networks towards developing chronic pain. So, advanced neuroimaging studies can powerfully aid explanation of a subject’s multidimensional pain experience, pain relief (analgesia) and even what makes them vulnerable to developing chronic pain. The application of this goes beyond the clinic and has relevance in courts of law, and other areas of society, such as in veterinary care. Relatively far less work has been directed at understanding what changes in the brain occur during altered states of consciousness induced either endogenously (e.g. sleep) or exogenously (e.g. anaesthesia). However, that situation is changing rapidly. Our recent multimodal neuroimaging work explores how anaesthetic agents produce altered states of consciousness such that perceptual experiences of pain and awareness are degraded. This is bringing us fascinating insights into the complex phenomenon of anaesthesia, consciousness and even the concept of self-hood. These topics will be discussed in my talk alongside my ‘side-story’ of life as a scientist combining academic leadership roles with doing science and raising a family.
The BHP Chronic Pain Health Integration Team: Helping those with chronic pain to access the support they need / A bit of a To and Fro with population pain science
Candy will provide an overview of Bristol Health Partners' Chronic Pain Health Integration Team which brings together clinicians, academics, patients and carers to focus on improving the lives of those with chronic pain and supporting those who provide chronic pain services or care. Tony will describe recent and ongoing studies that have been forward and reverse translating pain neuroscience from animal to human including functional imaging in patients, microneurography, industrial partnerships and trials of novel preventative approaches that are benefitting from the people, expertise and facilities available in Bristol and GW4.
Plasticity of Pain and Pleasure
What happens when the nervous system fails to adapt? Our perception of the world relies on a nervous system that learns and adapts to sensory information. Based on our experience we can predict what a wooden surface will feel like, that fire is hot, and that a gentle caress from a partner can be soothing. But our sensory experience of the world is not static – warm water can feel like fire on sunburned skin and the gentle brush of our clothes can be excruciating after an injury. In pathological conditions such as chronic pain, changes in nervous system function can cause normally innocuous sensory stimuli to be perceived as aversive or painful long after the initial injury has happened. These changes can sometimes be similar to the formation of a pain ‘memory’ that can modulate and distort our perception of sensory information. Our research program seeks to understand how fundamental processes that govern the formation and maintenance of plastic changes in the nervous system can lead to pathological conditions and how we can reverse engineer these changes to treat chronic conditions.
Targeting the Endocannabinoid System for Management of Chemotherapy, HIV and Antiretroviral-Induced Neuropathic Pain
Chemotherapeutic drugs (used for treating cancer), HIV infection and antiretroviral therapy (ART) can independently cause difficult-to-manage painful neuropathy. Paclitaxel, a chemotherapeutic drug, for example is associated with high incidence of peripheral neuropathy, around 71% of the patients of which 27% of these develop neuropathic pain. Use of cannabis or phytocannabinoids has been reported to improve pain measures in patients with neuropathic pain, including painful HIV-associated sensory neuropathy and cancer pain. Phytocannabinoids and endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), produce their effects via cannabinoid (CB) receptors, which are present both in the periphery and central nervous system. Endocannabinoids are synthesized in an “on demand” fashion and are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Various studies, including those from our group, suggest that there are changes in gene and protein expression of endocannabinoid molecules during chemotherapy-induced neuropathic pain (CINP), HIV and antiretroviral-induced neuropathic pain. Analysis of endocannabinoid molecule expression in the brain, spinal cord and paw skin using LC-MS/MS show that there is a specific deficiency of the endocannabinoids 2-AG and/or anandamide in the periphery during CINP. Various drugs including endocannabinoids, cannabidiol, inhibitors of FAAH and MGL, CB receptor agonists, desipramine and coadministered indomethacin plus minocycline have been found to either prevent the development and/or attenuate established CINP, HIV and antiretroviral-induced neuropathic pain in a CB receptor-dependent manner. The results available suggest that targeting the endocannabinoid system for prevention and treatment of CINP, HIV-associated neuropathic pain and antiretroviral-induced neuropathic pain is a plausible therapeutic option.
Neuro-immune interactions in pain and host defense
The Chiu laboratory focuses on neuro-immune interactions in pain, itch, and tissue inflammation. Dr. Chiu’s research has uncovered molecular interactions between the nervous system, the immune system and microbes that modulates host defense. He has found that sensory neurons can directly detect bacterial pathogens and their toxins to produce pain. Neurons in turn release neuropeptides that modulate immune cells in host defense. These interactions occur at major tissue barriers in the body including the gut, skin and lungs. In this talk, he will discuss these major neuro-immune interactions and how understanding them could lead to novel approaches to treat pain or inflammation.