Basic Science

Stress, Pain and Reward, Evolving Neuroscience with Therapeutic Implications

The role of stress in the propensity to chronic pain is increasingly recognized. Allostasis, described as achieving stability through change, is an adaptation that accommodates potential threats through a process of learning (conditioning). A state of chronic deviation of the regulatory system from its normal (homeostatic) operating level is defined as an allostatic state. Stressors in the development of an allostatic state could include childhood abuse, chronic painful illness or socioeconomic factors. Chronic pain, most notably chronic primary pain, is also seen as evolving through allostasis. A similar process of allostatic change is thought to occur as an adaptation to exogenous opioid use leading to tolerance, dependence and possibly also addiction. This workshop will describe new insights into central stress-induced processes that are still in discovery, and are increasingly revealed as important in the development of both chronic pain and addiction.

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Stress, Pain and Reward Interactions and Their Clinical Relevance

The focus of the other two speakers in the workshop will be on the neurobiological basis of stress, chronic pain (Navratilova) and opioid dependence (Koob).   Dr Ballantyne will review the clinical relevance of their findings.  She will describe recent clinical experience and clinical research that supports an important role for buprenorphine in the treatment of opioid dependence in patients with pain, as well as this drug’s additional antidepressant benefits.  Presumptively, it is the kappa-antagonism of buprenorphine that confers special benefit, where dynorphin and the kappa-opioid system are key participants in the stress-induced perturbations that will be described in the other two talks.  Because of its current high usage, buprenorphine will be the focus of this segment.   However, the potential antidepressant benefits of this and other kappa antagonists such as BTRX 335140 (BlackThorn Therpeutics) are still being realized and investigated and this segment will update the status of this research.  New behavioral approaches that aim to reverse fear- and stress-based brain learning will be mentioned in context, recognizing that pharmaceutical interventions may realize their greatest benefit when used to enhance the effects other interventions. 

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Opponent Process in Opioid Tolerance: Focus on Opioid Induced Hyperalgesia

Despite opioids’ potent analgesic effectiveness, their use is limited by detrimental neuroadaptations. Opioid tolerance is associated with opioid induced hyperalgesia (OIH) since its prevention restores opioid analgesic effects. Many features of opioid-induced hyperalgesia can be viewed in terms of adaptive response intended to normalize net activity by engaging opposing or compensatory regulatory mechanisms or signaling pathways to reduce opioid responses. This phenomenon refers to the opponent process theory. In this session, Dr Rivat will describe opponent process and how opponent process contributes to the adaptation of the analgesic effects of opioid. Numerous cellular and molecular changes arising from primary sensory neurons of the DRG mediate neuronal hyperexcitability produced by chronic morphine. This supports the development of long-term potentiation (LTP) in the spinal cord which depends on pre-synaptic NMDARs shown by electrophysiological studies. Chronic opioids cause adaptive plasticity in peripheral nociceptors, which in turn alters activity of downstream nociceptive networks (spinal cord LTP), leading to OIH.
Dr Rivat will highlight the role of the FLT3 (the Fms-LikeTyrosine kinase 3 receptor) receptor expressed in dorsal root ganglia in the development of OIH. He will present preclinical observations showing that the blockade of FLT3 receptor may increase morphine analgesic effect.

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Brain Opioid Circuits Modulating Pain Perception

It has increasingly been recognized that brain stress circuits interact with and modulate pain perception by regulating descending pain pathways and by altering the aversion/reward processes. Conversely, chronic pain may promote adaptations in the stress circuits that lead to increased susceptibility to other stressors. In this session, Dr. Navratilova will focus on recent preclinical investigations that demonstrate opposing roles of kappa and mu opioid circuits in modulation of pain. She will highlight the role of kappa opioid receptor neurotransmission in the amygdala and the cortex in promoting aversive aspects of ongoing pain and eliciting motivation to seek pain relief. In contrast to the pro-nociceptive function of kappa opioid signaling, the engagement of mu opioid circuitries in these brain regions supports analgesia by relieving pain aversiveness. Similarly, kappa and mu opioid signaling exert opposite effects on the descending pain pathways. Possible therapeutic implications of these findings for the development of non-addictive pain therapies will be discussed.

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2022 Genes, Environments and Development in Pain: Crossing the Translational Divide

How do genetic and environmental factors influence pain in early life and in turn influence pain experience in adulthood? Exposure to adverse experiences during early life are known to predispose to a wide variety of health issues of varying severity in later life, including chronic pain. The underlying neurobiological mechanisms that underlie these effects remain poorly understood. In this symposium we address these questions using pre-clinical models of early life adversity/adverse experience with clinically relevant behavioural and novel imaging techniques to reveal the changes in the brain affected by these early life events. Genetic factors linking adolescent pain with anxiety and other comorbidities will be addressed using human twin studies. Is there a shared genetic risk of pain and affective/cognitive disorders? Using the mouse as a model system we can probe the brain to reveal the cellular and molecular events underlying the long-term effects and address the fundamental question of how the environment shapes the brain.

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Biomarkers of Vulnerability and Resilience to Chronic Pain Following Early Life Adversity. A Longitudinal Imaging Study in Mice

Longitudinal studies of pre-term infants have revealed long-term effects that encompass altered sensitivity to pain and affective and cognitive responses to future pain, associated with changes in brain structure. Here, we use longitudinal MRI to study mice from early postnatal life into adulthood. Mice are imaged prior to undergoing an experimental surgical incision and then at points throughout the lifespan both prior and subsequent to adult surgical incision as a model of surgical pain. 

Using behavioural measures of sensory, affective and cognitive behaviours in tandem in the same cohorts of mice we have begun to understand how adverse experiences in early life influence how animals differ in later life.

The overall aim was to identify brain structures where changes predict adverse responses to painful events in later life and predisposition to pain chronicity.

Early life adverse events influence development and future responses to painful events. What creates vulnerability and resilience in the context of susceptibility to chronic pain? We identify changes in brain structures that predict vulnerability and resilience to subsequent pain chronicity, specifically when in development and what structures within the brain differ that predispose to differences in adult behaviour.

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Comorbid Chronic Pain, Mood, and Metabolic Disorders Arising from Early Life Stress Exposure in Mice

Exposure to early life stress has a significant and long-lasting impact on health outcomes later in life, leading to increased morbidity and mortality. Adults who report high adverse childhood events scores are more likely to present with chronic pain, mood disorders, obesity, and/or metabolic syndrome. Outcomes due to early life stress are largely attributed to alterations within the hypothalamic-pituitary-adrenal (HPA) axis, which lead to changes in glucocorticoid production, responsivity, and signaling. The hippocampus is an important negative regulator of HPA axis function and is especially susceptible to early life stress exposure. Our laboratory has developed and characterized a mouse model of neonatal maternal separation (NMS) to study outcomes related to early life stress. Here, we will present data demonstrating that NMS mice display evidence of urogenital hypersensitivity, as well as migraine-like behaviors, altered anxiety- and depressive-like behaviors, and increased adiposity both on a chow and high fat/high sucrose diet. Results from magnetic resonance imaging/spectroscopy (MRI/MRS) studies, as well as immunohistochemical investigation, have revealed decreased gray matter volume and neurogenesis in the hippocampus of NMS mice. Together, these results suggest that NMS in mice may provide an important translational model for understanding the mechanisms that contribute to early life stress-induced outcomes.

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Twin Studies as a Tool to Understand Adolescent Pain

Chronic pain often begins in childhood/adolescence and is accompanied by anxiety, depression. Clinicians often favour causal interpretations of this comorbidity (e.g., pain causes anxiety/depression). Studies of twin cohorts can test the likelihood of alternative explanations (i.e.: sharing of common genetic/environmental determinants vs. direct causation, e.g.: anxiety causes pain, or vice-versa), and estimate the relative contribution of genetic/environmental influences.
This presentation focuses on twin studies of adolescent pain (AP) and its relationship to anxiety, depression and substance use. It will discuss the following main findings:
-Although it is composed of multiple symptoms, AP is best represented as a unitary, homogenous dimension
-Canadian twin adolescents who are in a trajectory of ‘frequent AP’ are 4 times more likely to be prescribed an opioid at age >19 than those in a trajectory of ‘none-to-minimal’ pain
-AP co-occurs with anxiety, depression due to shared genetic/environmental risk factors, and direct causation (e.g.: anxiety causes pain, or vice-versa) appears to be a less likely explanation.
– Anxiety-depression together predict higher propensity to adolescent substance use
-Physician prescribed opioids for AP can be an entry point for substance diversion-misuse-dependence.

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News from the Brainstem: Functional Plasticity in Noradrenergic Nuclei upon Stress and Injury

Multiple lines of evidence demonstrate that one important mechanism underpinning chronic pain is dysfunction of brainstem-origin noradrenergic-control pathways encompassed by the descending pain modulatory system (DPMS). This workshop will detail the latest knowledge regarding the functionality of key noradrenergic nuclei that govern nociceptive processing in health and disease, as we unpick the maladaptive plasticity that initiates, maintains and/or progresses pain states. The locus coeruleus (LC), origin of a traditionally viewed inhibitory component of the descending pain modulatory system, takes centre stage. Beginning with Dr Kirsty Bannister, UK, novel data relating to reciprocity between the LC and other brainstem noradrenergic pathways will be discussed with reference to evidence for a ‘chronic pain generator’ LC role in the switch from health to disease. This will set the scene for Professor Esther Berrocoso, Spain, who will detail data regarding time dependent adaptations produced by nerve injury in LC-brainstem pathways, and their role in sensorial hypersensitivity and affective-related symptoms (anxiety and depression). Finally, in affective terms, Dr Jordan McCall, USA, will discuss the role of LC activity in acute stress-induced antinociception, with special focus on the separation of effects of LC activity that is required during stress, during nociception, or both for stress-induced antinociception.

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Reciprocity between Brainstem Noradrenergic Nuclei in Health and Disease

The aim of the presentation described herein is to inform the audience on the nature of the influence of the locus coeruleus (LC), a noradrenergic brainstem nucleus traditionally viewed as an inhibitory component of the descending pain modulatory system (DPMS), on spinal nociceptive processing. Recognising that ventral, but not dorsal, LC neurons project to the dorsal horn, the modular organisation of the LC lends itself to pain modulatory (inhibitory as well as facilitatory) mechanisms in the transition from acute to chronic pain. Interestingly, the mechanistic underpinning of this contrasting modulatory impact likely involves separate projection sites to key medullary nuclei that themselves govern distinct modulatory controls. Pinpointing the functionality of discrete top-down pathways is crucial for understanding the sensorimotor modulation in health (i.e. nociception) and disease (i.e. chronic pain). Thus, I will discuss changes in the reciprocity of noradrenergic nuclei governance, where tonic as well as evoked modulatory pathways will be considered (LC-spinal as well as DNIC circuits respectively), in animal models of chronic pain including neuropathy and cancer induced bone pain, where stage specific treatment approaches are crucial if pain is to be managed along the course of the disease.

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