DREADDING Pain: Excitatory and Inhibitory Neurons in the Periaqueductal Gray Modulate Pain
Material below summarizes the article Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray, published on March 17, 2017, in eNeuro and authored by Vijay K. Samineni, Jose G. Grajales-Reyes, Bryan A. Copits, Daniel E. O’Brien, Sarah L. Trigg, Adrian M. Gomez, Michael R. Bruchas, and Robert W. Gereau.
Pain is a conscious experience that encompasses sensory, emotional, and cognitive dimensions. Pain signals detected by nerve fibers in the skin, tissue, and peripheral organs are transmitted into the brain via the spinal cord. Once perception of pain occurs, several regions in the brain exert a powerful control of incoming pain signals in the spinal cord.
An important example of this is the lack of pain perception that can be experienced when people are in “life or death” situations. One of these brain regions, the periaqueductal gray (PAG), is an evolutionarily conserved structure in the midbrain. Electrical stimulation of the PAG causes profound pain relief, or analgesia. This robust analgesia is mediated, in part, by descending connections to other regions in the brainstem.
Previous studies have investigated the role of excitatory and inhibitory neurotransmitters in the PAG that mediate pain processing. Despite this knowledge, the specific roles of excitatory and inhibitory neurons in the PAG in pain modulation were unknown. In this study, we selectively manipulated the activity of these different neurons in the PAG to determine their role in pain perception.
To selectively manipulate neuronal activity in the PAG, we used a new approach called chemogenetics. This technique combines chemistry — using molecularly engineered receptors that only respond when we administer a normally inactive drug called clozapine-N-oxide — with genetics to restrict the expression of these receptors to different neurons in the brains of genetically modified mice. This powerful approach allows us to selectively increase or decrease the activity of specific types of neurons.
We first set out to determine whether chemogenetic activation or inhibition of PAG neurons alters pain thresholds in the mouse paw. Our study focused on pain responses to heating of the paw and mechanical sensitivity to poking of the foot. We found that when we activate both excitatory and inhibitory neurons in the PAG, they experienced pain relief. In contrast, inhibiting the same groups of neurons enhanced their pain.
Next, we focused on the roles of specific types of neurons in the PAG that might control pain sensitivity. We discovered that activation of excitatory neurons decreased pain while inhibiting them enhanced pain. In contrast, we found that increasing the activity of inhibitory neurons increased pain, while inhibiting them blunted pain. These results suggest that the balance between excitatory and inhibitory neurons in the PAG is critical for modulating pain processing.
Future studies will need to further examine the interplay between other neuronal populations within the PAG that can be defined with the expression of other makers, such as neuropeptides, to assess their roles in regulating pain processing.
These finding suggest that we might be able to design new drugs to selectively target different populations of neurons in the PAG — and perhaps the brain more broadly — to treat patients suffering from chronic pain.
Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray. Vijay K. Samineni, Jose G. Grajales-Reyes, Bryan A. Copits, Daniel E. O’Brien, Sarah L. Trigg, Adrian M. Gomez, Michael R. Bruchas, Robert W. Gereau. eNeuro Mar 2017, DOI: 10.1523/ENEURO.0129-16.2017