The periaqueductal gray, or PAG, is an area of gray matter that surrounds the cerebral aqueduct in the brainstem. Although it is associated with a number of functions, it is best known for its role in analgesia, or pain reduction. In this video, I discuss the PAG and the pathway by which it is thought to be able to inhibit pain signals from the spinal cord.
Where is the periaqueductal gray?
The periaqueductal gray, or PAG, is an area of gray matter found in the midbrain. The PAG surrounds the cerebral aqueduct (hence the name periaqueductal) and occupies a column of brainstem that stretches about 14 mm long. There are no obvious visible anatomical divisions within the PAG, but researchers have divided the PAG into four columns based on differences in connectivity and function: the dorsomedial, dorsolateral, lateral, and ventrolateral columns. For the sake of simplicity, however, below I will discuss the PAG as a whole instead of partitioning it using this columnar organization.
What is the periaqueductal gray and what does it do?
Although the functions of the PAG are complex and not fully understood, since the 1970s it has best been known for its role in the inhibition of pain. Indeed, some have argued that its identification as an "analgesia center" has hindered a more complete understanding of the functions of the PAG. An increasingly intricate appreciation of PAG function, however, has been emerging over the past few decades
When the PAG was first found to have an association with pain, it was observed as playing a role in pain transmission---or the sending of pain signals to the cortex---and not the mitigation of those signals. Eventually, the PAG would come to be much better recognized as an area important to pain inhibition. In the late 1960s, the first indication of the role of the PAG in pain suppression emerged from a study that found that stimulation of the PAG in rats allowed researchers to perform surgery on the rats without the use of anesthetics (and without the animals exhibiting signs of severe pain). Further studies found that PAG activation was associated with the inhibition of spinal cord neurons involved in pain signaling. By the mid-1970s, stimulation of the PAG was already being used as an experimental approach to treating chronic pain in human patients. The fact that some of these experiments reported success in the treatment of chronic pain supported the role of the PAG in analgesia. The patients involved in these experiments also often complained of a wide range of side effects linked to PAG stimulation, however, suggesting that many more functions than analgesia were connected to the PAG.
Still, due to the seminal findings involving the PAG and pain reduction, the PAG became best known for its role in analgesia. Although this has been a recognized function of the PAG for several decades, the full complexities of the mechanism underlying PAG-facilitated analgesia are still not completely understood. The main pathway seems to involve neurons that project from the PAG to nuclei of the medulla---primarily the raphe nuclei, which are clusters of serotonin-producing neurons. Activated raphe neurons project down to the spinal cord where they inhibit neurons in the dorsal horn of the spinal cord that are responsible for transmitting pain signals. This pathway seems to be involved in a variety of pain inhibition responses, including analgesia experienced during acutely stressful events and the pain relief we obtain from taking opioid painkillers.
Interest in the PAG's role in pain inhibition has caused the other known functions of the PAG to often be overlooked; it's clear, however, that the PAG is involved in much more than just analgesia. For example, the PAG appears to play a part in the regulation of heart rate and blood pressure, and it is thought that the PAG may help to adjust cardiovascular activity in the context of particular emotional experiences. The PAG also seems to contribute to a number of other autonomic processes, and it is important to the control and contraction of the bladder in humans and other animals. The PAG plays a role in the production of vocalizations; stimulation of the PAG can elicit vocalizations in animals and lesions of the PAG can disrupt them in humans and other animals. In an attempt to understand the contributions of the PAG to vocalizations, some have hypothesized that the PAG is important to coordinating respiratory and laryngeal motor patterns that facilitate the production of vocalizations. The PAG also seems to be involved with emotional responses. It appears to be especially likely to be infuential in the production of fearful and defensive reactions, as stimulation of the PAG can elicit these types of reactions in a variety of animals; human participants also displayed activation of the PAG when a threat came closer to them.
There are still many other functions associated with the PAG that have not been mentioned here. Thus, despite being a relatively small area of the brain, the PAG is densely interconnected with various other brain regions, and seems to be involved in a diverse range of functions. It is therefore understandable why some researchers believe calling it an "analgesia center" is representative of a limited perspective on the PAG.
References (in addition to linked text above):
Carrive P, Morgan MM. Periaqueductal Gray. In: Mai JK and Paxinos G, eds. The Human Nervous System. 3rd ed. New York: Elsevier; 2012.
Spicy food—you either love it or hate it. Whichever group you fall into, though, there’s a good chance you’ve never thought about how intriguing a natural deception it really is. When we eat spicy food we may experience a variety of sensations (depending on the specific cuisine) ranging from tingling to numbness to painful burning. Yet, a short time later the feeling disappears, leaving no redness, scarring, or irritation behind, indicating that the previous unpleasantness we experienced was—literally—all in our heads.
The substance responsible for the burning sensation one may experience when eating chili or buffalo wings is known as capsaicin. It was identified in the 1800s, and a whole family of similar molecules, called capsaicinoids, were discovered in chili peppers in the 1960s. While capsaicin is an irritant to mammals, it has analgesic properties in birds when they consume it. Chili pepper seeds are broken down in the digestive tracts of mammals. Birds, however, pass the seeds intact. Thus, the capsaicin deters mammalian feeders and makes the peppers more palatable to birds, allowing the seeds to be dispersed efficiently through bird migrations. Hence, the burning feeling caused by capsaicin is probably a mechanism that evolved to promote seed dispersal.
It wasn’t until the late 1990s, however, that scientists began to unravel the mystery behind the phantom sensation caused by capsaicin. To understand it necessitates a little knowledge about neurophysiology. So, I’ll try to summarize half a semester of neurophys in a few short paragraphs.
Neurons (and some other types of cells) communicate with one another through pulses of voltage called action potentials. A neuron maintains a certain regular voltage, known as its resting potential. The membrane of a neuron is broken up by apertures called ion channels. When they are open, certain charged particles can pass in or out of them (which particles and to what extent depends on the type of channel and a number of other factors).
Neurons are influenced primarily by four types of ions: K+ and organic anions (A-) that are concentrated inside the cell, and Na+ and Cl-, which are for the most part outside of the cell. The resting potential across a neuron’s membrane is usually about –70mV. This potential is maintained by a sensitive pump that constantly pulls K+ in, while sending Na+ out.
When a neuron is excited, voltage-dependent ion channels quickly open that allow floods of Na+ into the cell. This causes a change in the voltage of the neuron, referred to as depolarization. The rapid depolarization is the trigger that sends a wave of voltage, the action potential, down the axon of the neuron. If it is strong enough, it will reach the end of the neuron, causing the release of neurotransmitter, which binds to surrounding neurons to open their ion channels, resulting in depolarization, and so on.
So, back to buffalo wings, chili, and capsaicin. Capsaicin is a ligand that binds to a specific receptor, the TRP vanilloid receptor subtype 1 (TRPV1). This receptor can also be stimulated with actual heat and physical injury. When it is activated, it opens ion channels that depolarize nerve cells by allowing an influx of Na+. This produces action potentials that travel to the brain and produce what is, in this case, a false sense of pain.
If you’ve ever eaten Szechuan peppers, you’ll know that the feeling they evoke is different than that of chili peppers. Szechuan peppers cause a tingling, sometimes numbing, feeling. Instead of capsaicin, their active ingredient is hydroxy-alhpa-sanshool (sanshool). How sanshool acts to produce its numbing effect was somewhat of an enigma until a study published last week in Nature Neuroscience offered an explanation.
According to the authors of the study, sanshool acts on a different group of neurons than capsaicin. Capsaicin affects small-diameter sensory neurons that express proinflammatory peptides (which are responsible for the pain), but sanshool acts on large diameter neurons usually associated with proprioception and detection of touch or vibration.
Sanshool was thought to have an effect by opening Na+ channels, in a manner similar to capsaicin. The Nature study, however, found that sanshool actually inhibits K+ channels. The result is still an action potential, but through a different mechanism.
You may be thinking this is a lot of research money being wasted to figure out why food is spicy. But understanding these subtleties of the sensory system is important in that it brings us closer to an overall comprehension of how our senses work. Also, both capsaicin and sanshool have applications as analgesics (ironically capsaicin can reduce pain when applied topically, possibly because it floods the sensory neurons to the point where they go numb).
A side note: A couple of years ago a Harvard researcher, Clifford Woolf, made a novel suggestion. Since the most highly abused prescription drugs like OxyContin and Ritalin generally lead to addiction when users begin snorting them, why not mix capsaicin in with them? This, Dr. Woolf asserted, would not affect the oral digestion of the pills but would make snorting them like “snorting an extract of 50 jalapeno peppers”.
One thing that has always amazed me about pills like these is how amenable they are to being crushed up and snorted. Elizabeth Wurtzel, in her book about Ritalin addiction More, Now Again: A Memoir of Addiction implies that pharmaceutical companies purposely make their drugs like this in order to increase demand and black market consumption. I don’t know if I agree with her or not yet, but when there seem to be options to change the consistency of the pill, or when deterrents like adding capsaicin are available, and they are ignored, it does become suspicious.
Bautista, D.M., Sigal, Y.M., Milstein, A.D., Garrison, J.L., Zorn, J.A., Tsuruda, P.R., Nicoll, R.A., Julius, D. (2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neuroscience, 11 (7), 772-779. DOI:10.1038/nn.2143