Researchers have pinpointed the precise pathway in the brain that suppresses pain in times of threatening situations.
The study in mice, published today as a Reviewed Preprint in eLife, is described by editors as a timely and important contribution to our knowledge of the circuit mechanisms of fear-conditioned analgesia – the natural suppression of pain in dangerous situations. They say the strength of the evidence is compelling, and the work provides key insights of interest to systems and behavioural neuroscientists, especially those interested in emotional behaviour, pain, and/or midbtrain function.
In threatening situations, fear-conditioned analgesia is an essential survival response. A midbrain structure called the periaqueductal gray matter (PAG) plays a key role in this process. Within this structure, the ventrolateral periaqueductal gray matter (vIPAG) is known to help modulate pain and emotional responses. The PAG receives many signals from brain regions involved in fear processing, which it then projects to the spinal cord through another key structure called the rostral ventromedial medulla.
“The vIPAG is ideally located in the brain to allow emotional regulation of pain behaviour, yet the underlying neuronal circuits and mechanisms are largely unknown,” says co-lead author Nanci Winke, at the time of the study a postdoctoral researcher at Neurocentre Magendie, University of Bordeaux, and INSERM, France, and now at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. “We developed a unique behavioural model where a cue-driven defensive state promotes changes in pain sensitivity and then used this to determine the precise circuits used to suppress pain during periods of fear.”
Winke served as lead author of the study alongside Frank Aby, a postdoctoral researcher in the Institute of Neurodegenerative Diseases, University of Bordeaux, and Daniel Jercog, at the time of the study a postdoctoral researcher at the Neurocentre Magendie, University of Bordeaux, and INSERM. Jercog is now at the Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
To explore the contribution of different vlPAG cells in fear-modulated pain behaviour, the researchers conditioned a group of mice to associate an auditory cue with a fearful event, while a control sound was not associated with any event. They then compared how sensitive these mice were to pain when exposed to the conditioned or neutral cue. They observed a significant delay in the pain response when mice were exposed to the fear-inducing cue, compared to the control stimulus. This suggests that the presence of a conditioned threat-predicting cue can selectively induce analgesia.
Next the team sought to determine the cell types within the vlPAG that mediated this effect, focusing on the most abundant group – somatostatin (SST)-expressing interneurons. They used an approach called optogenetics – where light is used to control neuron activity – to selectively modulate SST-positive cells in the vlPAG. They noted that inhibiting the SST-positive cells increased the time to pain response when mice were exposed to the threat-cue and the control stimulus.
These results suggest that SST-positive vIPAG cells could be part of a circuit involved in the fear regulation of pain suppression. But to see whether these cells also inhibit pain in the absence of fear, the team used optogenetics to explore electrical signals from vIPAG cells to the spinal cord. They found that activating the SST-positive vIPAG cells increased nociceptive response transmission – that is, the detection of painful stimuli – in the spinal cord whereas inhibiting the cells decreased nociception.
The team next set out to determine whether SST-positive vIPAG cells mediate their effects on analgesia through the structure called the rostral ventromedial medulla (RVM) or by contacting other cells directly in the spinal cord. To do this, they mapped neural connections with special tracers that move along the nerves. Indeed – as they expected – this revealed RVM cells projecting to a region of the spinal cord involved in pain regulation, with close involvement of the SST-positive vlPAG cells.
While the study sheds light on a novel brain circuit involved in pain suppression during cued fear, the authors note that different types of emotional responses – such as those triggered by environmental context or chronic stress – may involve separate pathways. Further studies will be needed to explore whether these findings apply to other forms of emotionally driven pain perception, and how they might translate to humans.
“Our results identify a new circuit between the midbrain and brainstem involving cells that can regulate both fear expression and analgesia,” says co-senior author Cyril Herry, Principal Investigator at the Neurocentre Magendie, University of Bordeaux, and INSERM. “Given the link between anxiety and pain-related disorders, knowledge about the circuits underpinning emotional regulation of pain disorders is urgently needed. The next step will be to understand how this circuit is affected by different negative emotional states such as depression or stress. These findings should aid our understanding of the interplay between pain and emotion and advance the development of more effective, targeted analgesic therapies.”
Herry served as senior author of the study alongside Stephane Valerio, a postdoctoral researcher at the Neurocentre Magendie, University of Bordeaux, and INSERM, and Pascal Fossat, a Professor at the Institute of Neurodegenerative Diseases, University of Bordeaux.
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