Mechanisms of Pain Revealed by Latent Sensitisation Models

Session Title: Mechanisms of Pain Revealed by Latent Sensitisation Models

Topic: BASIC SCIENCE

Description of Workshop: In rodents and humans, hyperalgesic priming of nociceptive neurons can be induced by injury, inflammation or stress that cause measurable acute hypersensitivity. These salient events underpin latent sensitisation where the acute pain episode confers a long-lasting vulnerability to developing an exaggerated sensitivity to subsequent noxious stimuli, with an increased magnitude and/or duration of hypersensitivity. Preclinical models of latent sensitisation offer the ability to (1) Study the transition from acute-to-chronic pain, (2) Reproduce the episodic nature of pain, (3) Model the response of the nociceptive system to repeated noxious stimuli.

The priming stimulus used in latent sensitisation models determines both the magnitude and duration of latent hypersensitivity following subsequent insults. The response to a subsequent insult is often greater in intensity and longer in duration (extending from hours to weeks) compared to what is observed in unprimed conditions. It is now well established that priming events can modulate response profiles of sensory neurons and induce reorganization of the transcriptional landscape of nociceptors – phenomena that contribute to the increased susceptibility of nociceptor sensitisation to subsequent subthreshold stimuli. Latent sensitisation has also been shown to underlie nociceptive responsiveness to stimuli that would normally produce analgesia.

This session will review how various preclinical models of latent sensitisation have provided important mechanistic insights into aberrant nociceptor activity and altered central nervous system circuitry underlying the transition from acute to chronic pain. The session also proudly highlights data generated across three continents and contributed by researchers ranging from early-career scientists to established investigators. The speakers will describe different experimental hyperalgesic priming paradigms in rodent models where distinct priming stimuli can produce acute nociceptive pain and enable latent sensitisation of nociceptive neurons. The talks will encompass in vivo and in vitro assessments of nociceptor activity, omics-based profiling of primed nociceptors, and central nervous system engrams that maintain latent hypersensitivity. The following datasets arising from latent sensitisation studies will be addressed:

• Dissecting the roles of amygdaloid and thalamic nuclei in the development of allostatic load and stress- and anxiety-related nociceptive behaviours in acute and persistent muscle pain
• Elucidating the contributions of endogenous systems, including peripheral opioid receptor activity and macrophage colony-stimulating factors, in acute and persistent post-operative pain
• Employing TRAP-seq (Translating Ribosome Affinity Purification sequencing) with Cre-mediated tagging of peripheral and central nervous system neurons to define the translatome of neuronal engrams of latent sensitisation

In this session, attendees will gain an integrated understanding of the cellular and molecular mechanisms underlying the transition from acute to chronic pain states. The workshop aims to facilitate knowledge transfer from the presenting researchers who are experienced in the technical application of latent sensitisation models, enabling attendees to:

• Learn how different exteroceptive and interoceptive events can prime nociceptive neurons to develop latent sensitization
• Understand how key endogenous opioid systems and innate immune cell functions contribute to modulation of latent sensitivity.
• Explore how translational reorganization in nociceptive neurons is linked to the development of latent sensitivity and maintenance of negative affect

Speakers