Neurons in the Brainstem Modulate Pain Sensation
Post by Baldomero B. Ramirez Cantu
The takeaway
This study provides evidence that neurons located in the medulla oblongata are involved in modulating pain sensation. These neurons exert their inhibitory effects through a tract that connects the cortex and spinal cord, regulating the perception of pain.
What's the science?
The detection of stimuli that could be perceived as painful typically begins with nociceptive neurons in the peripheral nervous system, which transmit signals to higher brain centers to produce an appropriate sensory response. However, the perception of pain is not fixed and can be modulated to suit a specific context. For example, individuals may exhibit a higher pain tolerance while pursuing a goal, or a lower pain tolerance while a particular region of the body is undergoing repair following an injury. The medulla is thought to play a role in top-down pain modulation. This week in Nature Neuroscience, Gu and colleagues elucidate the mechanisms by which neurons in the ventrolateral medulla (VLM) play a role in modulating pain sensation via the locus coeruleus-spinal cord (LC-SC) pathway.
How did they do it?
The authors used a variety of techniques to probe the role of the medulla oblongata in pain sensation and regulation in adult mice. First, the authors used the neural activity marker c-Fos to confirm the activation of neurons in the ventrolateral medulla (VLM) in response to painful stimulation with capsaicin, the active component of chili peppers. They then used multiple-label immunohistochemistry staining and viral vector tracing to further characterize the identity and connectivity of the pain-responding neuronal population found in the VLM. Next, the authors used viral vectors to express a fluorescent calcium indicator, GCaMP6, in VLM neurons, which allowed them to observe neuronal activity in-vivo using fiber photometry. Finally, the authors used chemogenetics (DREADDs) and optogenetics to manipulate neural activity in these circuits.
What did they find?
The authors observed an increase in c-Fos expression in the caudal VLM following capsaicin stimulation. Double-label immunohistochemistry revealed that neurons labeled for tyrosine hydroxylase, a crucial enzyme in the synthesis of neurotransmitters such as dopamine, were also labeled for c-Fos. Further analysis confirmed their molecular identity as noradrenergic and dopaminergic neurons. Anterograde viral tracers injected in the spinal cord showed no projections to the noradrenergic neurons of the cVLM, supporting the role of the cVLM in supraspinal processing of painful stimuli. In-vivo fiber photometry showed that cVLM-TH neurons responded to various noxious stimuli including capsaicin, noxious heat, and noxious mechanical pinch, indicating their preference for noxious stimuli.
Modulating the activity of cVLM-TH neurons modified mice’s behavioral response to noxious stimuli. Specifically, chemogenetic activation of cVLM-TH neurons led to a suppression of responses to heat-detection tests. Conversely, chemogenetic suppression of the activity of cVLM-TH neurons resulted in a reduction of the latency of withdrawal responses in heat-detection tests, suggesting that these neurons normally provide inhibition to this nociceptive response. In other words, inactivating cVLM-TH neurons caused the mice to withdraw from a heating plate earlier, while activating them delayed their withdrawal. These findings were recapitulated using optogenetic manipulation of the neurons.
Viral tracing revealed that cVLM-TH neurons project strongly to the locus coeruleus (LC), a major source of norepinephrine release, and a brain region long implicated in exerting analgesic effects via its projections to the spinal cord. To further understand the connectivity between cVLM-TH and LC neurons, the authors employed a combination of viral tracing, photometry, and electrophysiological techniques. Activation of cVLM-TH neurons using several modalities revealed responses in LC-SC neurons that project to the spinal cord. These findings suggest that cVLM-TH neurons modulate nociceptive signals via their connections with LC-SC neurons in the spinal cord. The authors then conducted an experiment to investigate the role of norepinephrine in the cVLM-TH mediated analgesic effects. They blocked norepinephrine transmission while chemogenetically activating the cVLM and observed that there was an increase in heat sensitivity. These activation and subsequent inactivation manipulations provide evidence for the involvement of norepinephrine released by LC neurons in the analgesic effects mediated by cVLM-TH.
What's the impact?
This study contributes to the understanding of the neural basis of pain and could inform the development of new analgesic treatments. Overall, this study has the potential to have a significant impact on the field of pain research.
