Unraveling the Cholinergic Modulation of Pain: A Path to Non-Opioid Analgesia


Pain management has long been a challenge in the field of medicine, with opioids like morphine and fentanyl being effective but fraught with undesirable side effects, abuse potential, and the development of tolerance and withdrawal symptoms.

The widespread availability of opioids has contributed to the opioid epidemic, highlighting the urgent need to explore alternative, non-opioid approaches to pain management.

One such approach involves investigating the descending pain-modulatory pathway, a neural circuit that plays a pivotal role in regulating pain perception. At the heart of this circuit lies the ventrolateral periaqueductal gray (vlPAG), a region known for its profound analgesic effects when manipulated.

This article delves into the intricate world of cholinergic modulation in the vlPAG and its potential as a novel avenue for pain relief. It begins by addressing the current challenges associated with opioids in pain management and the necessity to uncover alternative strategies for addressing chronic pain.

It then explores the significance of the vlPAG in the descending pain-modulatory pathway and its responsiveness to various interventions, including opioids. Finally, it delves into the role of acetylcholine (ACh) as a key neuromodulator in the vlPAG, unveiling its potential as a non-opioid analgesic target.

Understanding Pain Processing in the vlPAG

The descending pain-modulatory pathway is a complex neural circuit that deciphers and modulates pain signals based on both internal states and external stimuli. At the core of this pathway, the vlPAG serves as a vital regulator.

Manipulating the activity of vlPAG neurons has been shown to produce profound analgesia, predominantly by modulating projections to regions like the rostral ventromedial medulla (RVM) and locus ceruleus (LC). However, despite the importance of the vlPAG in pain modulation, its neuronal ensemble dynamics in acute and chronic pain states remain relatively unexplored.

Acetylcholine Emerges as a Key Player

Acetylcholine (ACh) has long been recognized as a crucial neuromodulator that influences cellular signaling and neuronal excitability across various brain regions to shape behavior. However, its role in pain modulation, particularly within the vlPAG, has remained a mystery. While cholinergic terminals in the vlPAG have been identified anatomically, their functional significance has remained elusive.

This study endeavors to unravel the mysteries of ACh in the vlPAG. Utilizing advanced techniques, including the novel ACh biosensor GRABACh 3.0, researchers have delved into ACh release dynamics under different pain states. The source of ACh in the vlPAG has been identified, and the study investigates how manipulating ACh levels can alleviate both somatic and affective aspects of pain.

The Receptor Mechanisms of Cholinergic Pain Relief

With ACh’s role in pain modulation established, the next question is how it exerts its analgesic effects. This study explores the receptor and intracellular signaling pathways responsible for mediating these effects. It is discovered that α7 nicotinic acetylcholine receptors (nAChRs) play a central role in reversing pain-induced maladaptive hyperexcitability in vlPAG neuronal ensembles. This unexpected finding sheds light on a novel mechanism for pain relief.

Preserving Analgesic Potency Beyond Opioid Tolerance

One of the remarkable findings of this investigation is that the analgesic potency of descending pain control circuits remains intact even after opioid tolerance has developed. This suggests that cholinergic modulation offers a promising avenue for pain relief that is not compromised by opioid tolerance, withdrawal symptoms, or the risk of addiction.

A Complex Interplay of Cholinergic and Opioid Systems

This research has also uncovered intriguing insights into the interplay between cholinergic and opioid systems in pain modulation. It was observed that while opioids primarily inhibit GABAergic interneurons in the vlPAG, a subset of vlPAG neurons was inhibited by morphine administration. These effects were lost under opioid-tolerant conditions, suggesting that the two systems interact in complex ways.

Unveiling the Nuances of Cholinergic Physiology

The study’s findings challenge conventional wisdom about cholinergic physiology. Firstly, it was unexpected that painful experiences would lead to decreased ACh levels in the vlPAG, as typically, salient stimuli increase ACh release. This suggests an unexplored role for baseline cholinergic tone in maintaining an equilibrium of pain sensitivity.

Secondly, cholinergic signaling in the central nervous system has remained enigmatic due to the dual nature of cholinergic synaptic transmission, involving both bulk volume and fast synaptic transmission. The research employs innovative methods to clarify these mechanisms.

Looking Ahead: Potential Implications

The exploration of cholinergic modulation in the vlPAG opens up new avenues for pain management. This research may ultimately lead to the development of non-opioid analgesic treatments that are not only effective but also devoid of the adverse effects associated with opioids. Moreover, it prompts further investigations into the potential role of cholinergic circuits in other neurological conditions, such as ADHD and cognitive comorbidities in chronic pain states.


Chronic pain is a complex phenomenon that involves intricate neural circuits and signaling pathways. The ventrolateral periaqueductal gray (vlPAG) emerges as a crucial hub in the descending pain-modulatory pathway. This study sheds light on the previously unexplored role of acetylcholine (ACh) in pain modulation within the vlPAG. It uncovers the source of ACh, identifies receptor mechanisms responsible for pain relief, and demonstrates the preservation of analgesic potency even in the face of opioid tolerance.

The findings offer hope for the development of non-opioid analgesic treatments that can alleviate pain without the associated risks of opioids. They also open up new avenues for research into the complex interplay between cholinergic and opioid systems in pain modulation. Ultimately, this work deepens our understanding of pain control circuits and provides a foundation for the exploration of novel molecular and cellular targets in the quest for effective pain management strategies.

reference link: https://www.cell.com/neuron/fulltext/S0896-6273(23)00627-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS089662732300627X%3Fshowall%3Dtrue#secsectitle0100


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