Chronic Pain Mechanisms and Novel Drug Targets

May 8-15, 2027

Director: A. Vania Apkarian

Northwestern University, Chicago, USA

Faculty:

Grégory Scherrer, University of North Carolina, Chapel Hill, USA

Didier Bouhassira, Ambroise Paré Hospital, Boulogne-Billancourt, France

Andrea Hohmann, Indiana University, Bloomington, USA

Ulrike Bingel, University Medicine Essen, Germany

Giandomenico Iannetti, IIT, Rome, Italy & University College London, UK

Christof Koch, Allen Institute & Tiny Blue Dot Foundation, Seattle, USA

A. Vania Apkarian, Northwestern University, Chicago, USA

During this Advanced Course, the neural substrates of pain, from nociception to limbic and cortical circuits, will be thoroughly covered, including the latest ideas pitting localizationist models of perception to perception, engaging the whole nervous system all the time. The discussion will incorporate evidence that can be derived regarding the understanding of pain with fMRI and physiology across species. The latest evidence regarding the mechanisms of the transition from acute to chronic pain will be a major topic, which will be critically analyzed.

Focus will also be placed on the fundamental statistical methods applied to studying pain, including the latest machine learning approaches and multivariable techniques and the extent of their validity and interpretability.

The interplay between fundamental research and its clinical exploitation is a particularly important aspect of pain research. For this reason, dedicated sessions will delve into the latest approaches for drug development, especially for chronic pain, non-pharmaceutical approaches for managing pain, and clinical trial designs.

Pain as a subjective perceived or experienced state continues to influence ideas of what consciousness is and, in turn, defines our social discourse of who we are and how we treat each other and other organisms. The ongoing debate regarding several issues, including whether species like the octopus or the bee are conscious, is intimately linked to the science of pain. This will also be an important component of the Advanced Course.

Ulrike Bingel

Placebo and nocebo effects: how expectations shape health and treatment outcomes in pain and beyond

This session covers the complex psychoneurobiological mechanisms underlying placebo and nocebo effects in pain and beyond. Drawing on behavioral paradigms, pharmacological modulation studies, and advanced neuroimaging approaches I will demonstrate how expectations and prior treatment experiences—key drivers of placebo and nocebo responses—shape pain trajectories and the response to analgesic treatment. The talk will also examine how placebo and nocebo effects interact with active pharmacological treatments, influencing both therapeutic efficacy and the occurrence of side effects with important implications for clinical settings as well as the design, conduct, and
interpretation of placebo-controlled randomized controlled trials. Finally, key open questions, persistent challenges, and future directions in this field will be addressed and jointly discussed.

Didier Bouhassira

Challenges and opportunities of clinical pain research: from diagnosis to the development of new treatment options.

This course will present an in-depth exploration of chronic pain for clinicians and basic scientists seeking to bridge the gap between fundamental research and clinical practice. We will begin by examining core concepts related to the definition and distinctive features of chronic pain compared to acute pain, before addressing the classification of major pain syndromes, nociceptive, neuropathic, and nociplastic, along with their putative pathophysiological mechanisms and current approaches to clinical assessment. We will then critically review the landscape of available therapeutic strategies, encompassing both pharmacological and non-pharmacological interventions. Particular emphasis will be placed on emerging pharmacological agents (e.g. new sodium channel blockers), as well as novel non-pharmacological neuromodulatory approaches such as non-invasive brain stimulation techniques (rTMS, tDCS and transcranial ultrasound stimulation). Finally, we will address the broader challenges facing clinical pain research, with a focus on the pressing need to develop more personalized, mechanism-based treatment strategies grounded in pathophysiological criteria, which remains central to advancing the field.

Christof Koch

The Conscious Experience of Pain and its Neuronal Correlates

What accounts for subjective, conscious experience? All experiences, such as being in pain, bored, or in love, are constructs. They are not given by a simple mapping between the world and the mind. Instead, experiences are shaped by genetic factors, environmental conditions, lifetime experiences such as early childhood trauma, expectancy (as in placebo and nocebo effects), and sensory input.

I will discuss the Integrated Information theory (IIT) of consciousness. Unlike contemporary theories of consciousness based on computational functionalism, IIT takes a purely operational approach rooted in causal power. IIT argues that the neuronal correlates of consciousness, the maximum of intrinsic cause-effect power, are located to specific regions of cortex with particular types of connectivity, such as the posterior hot zone. I will discuss experimental progress achieved in locating the footprints of such and in reliably detecting the presence of covert consciousness in patients with Disorder of Consciousness.

Grégory Scherrer

Neural Circuits and New Therapeutics for the Multiple Dimensions of Pain

Pain is far more than a simple sensory signal; it functions as a sophisticated alarm and teaching system that orchestrates adaptive physiological and behavioral responses essential for survival. For these responses to effectively protect the organism, noxious events must be precisely localized and discriminated from innocuous stimuli, imbued with an aversive emotional valence that drives avoidance and protective behaviors, and cognitively evaluated to identify their origin and anticipate future threats. These distinct dimensions—sensory-discriminative, affective-motivational, and cognitive-evaluative—together transform raw nociceptive input into the complex, multi-faceted
experience we recognize as pain. In this lecture, we will explore the primary afferent, spinal, and supraspinal neural circuits that generate and integrate each of these core dimensions of pain. Drawing on landmark studies in both animal models and human subjects, we will trace the journey from classical anatomical mapping of pain pathways to contemporary insights at the level of molecularly defined neuronal subtypes and circuit-specific mechanisms. Finally, we will critically examine how these mechanistic advances are reshaping therapeutic strategies, offering new hope for developing more effective, targeted, and safer treatments for the diverse spectrum of acute and chronic pain conditions that continue to challenge patients and clinicians alike.

Andrea Hohmann

Harnessing the Endocannabinoid System to Combat Pain

The opioid epidemic has led to a resurgence of interest in medical marijuana as an analgesic strategy. Here, I review therapeutic strategies that target the endocannabinoid signaling system that offer considerable promise for suppressing pathological pain without the unwanted effects of THC in cannabis. The endocannabinoid system consists of endocannabinoids, cannabinoid receptors and the enzymes that control the biosynthesis and deactivation of endocannabinoids.  This system offers an array of therapeutic targets for drug development. I will highlight foundational studies documenting that cannabinoids act at a neural level to suppress pain, and evidence that endocannabinoids are mobilized on demand to produce adaptive changes in pain responsiveness. These contributions provide a foundation for the development of brain-permeant and peripherally restricted inhibitors of endocannabinoid deactivation. I will introduce phytocannabinoids, with an emphasis on THC and CBD, and address putative mechanisms of analgesic action as well as limitations of pharmacological strategies.  I will address the therapeutic potential of peripheral cannabinoid analgesic mechanisms and CB2 cannabinoid receptor signaling for suppressing neuropathic and inflammatory pain, and the therapeutic promise of CB2 antibody agonists as a therapeutic strategy. Finally, I will address the therapeutic promise of biased signaling and positive allosteric modulation of CB1 cannabinoid receptor signaling as an analgesic strategy. The focus of this Advanced Course is to identify promising analgesic strategies with the potential to offer a more circumscribed and potentially desirable therapeutic profile compared to orthosteric CB1 agonists.