The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in
autonomic function,
motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for descending
pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
modulation. It has
enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephali ...
-producing cells that suppress pain.
The periaqueductal gray is the
gray matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingui ...
located around the
cerebral aqueduct
The cerebral aqueduct (aqueductus mesencephali, mesencephalic duct, sylvian aqueduct or aqueduct of Sylvius) is a conduit for cerebrospinal fluid (CSF) that connects the third ventricle to the fourth ventricle of the ventricular system of the brai ...
within the
tegmentum
The tegmentum (from Latin for "covering") is a general area within the brainstem. The tegmentum is the ventral part of the midbrain and the tectum is the dorsal part of the midbrain. It is located between the ventricular system and distinctive b ...
of the
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
. It projects to the
nucleus raphe magnus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
, and also contains descending autonomic tracts. The ascending pain and temperature fibers of the
spinothalamic tract
The spinothalamic tract is a part of the anterolateral system or the ventrolateral system, a sensory pathway to the thalamus. From the ventral posterolateral nucleus in the thalamus, sensory information is relayed upward to the somatosensory cor ...
send information to the PAG via the
spinomesencephalic tract
The spinotectal tract (spinomesencephalic tract, spinotectal fasciculus, spino-quadrigeminal system of Mott) arises in the spinothalamic tract and terminates in the inferior and superior colliculi.
It is situated ventral to the lateral spinothala ...
(so-named because the fibers originate in the
spine and terminate in the PAG, in the
mesencephalon
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...
or midbrain).
This region has been used as the target for
brain-stimulating implants in patients with chronic pain.
Role in analgesia
Stimulation of the periaqueductal gray matter of the midbrain activates
enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephali ...
-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT (
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
) released from the
raphe nuclei descends to the
dorsal horn of the spinal cord where it forms excitatory connections with the "inhibitory
interneuron
Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. I ...
s" located in Laminae II (aka the
substantia gelatinosa
The apex of the posterior grey column, one of the three grey columns of the spinal cord, is capped by a V-shaped or crescentic mass of translucent, gelatinous neuroglia, termed the substantia gelatinosa of Rolando (or SGR) (or gelatinous substanc ...
). When activated, these interneurons release either enkephalin or dynorphin (endogenous opioid neurotransmitters), which bind to
mu and
kappa opioid receptor
Kappa (uppercase Κ, lowercase κ or cursive ; el, κάππα, ''káppa'') is the 10th letter of the Greek alphabet, representing the voiceless velar plosive sound in Ancient and Modern Greek. In the system of Greek numerals, has a value ...
s, respectively, on the axons of incoming C and A-delta fibers carrying pain signals from
nociceptor
A nociceptor ("pain receptor" from Latin ''nocere'' 'to harm or hurt') is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sens ...
s activated in the periphery. The activation of the mu-opioid receptor inhibits the release of
substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...
from these incoming first-order neurons and, in turn, inhibits the activation of the second-order neuron that is responsible for transmitting the pain signal up the spinothalamic tract to the ventroposteriolateral nucleus (VPL) of the thalamus. The nociceptive signal was inhibited before it was able to reach the cortical areas that interpret the signal as "pain" (such as the anterior cingulate). This is sometimes referred to as the
Gate control theory of pain and is supported by the fact that electrical stimulation of the PAG results in immediate and profound
analgesia
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...
. The periaqueductal gray is also activated by viewing distressing images associated with pain.
Role in defensive behavior
Dorsal PAG neurons are activated during various defensive behaviors. Stimulation of the dorsal and lateral aspects of the PAG can provoke defensive responses characterised by freezing immobility, running, jumping,
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
, and increases in blood pressure and
muscle tonus
In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sullivan, S. B. (2007). ...
. In contrast, stimulation of the caudal ventrolateral PAG can result in an immobile, relaxed posture known as
quiescence
Quiescence (/kwiˈɛsəns/) is a state of quietness or inactivity. It may refer to:
* Quiescence search, in game tree searching (adversarial search) in artificial intelligence, a quiescent state is one in which a game is considered stable and unl ...
, whereas its inhibition leads to increased locomotor activity.
Lesions of the caudal ventrolateral PAG can greatly reduce
conditioned freezing, whereas lesions of the dorsal aspect can reduce innate defensive behavior, virtually "
taming
A tame animal is an animal that is relatively tolerant of human presence. Tameness may arise naturally (as in the case, for example, of island tameness) or due to the deliberate, human-directed process of training an animal against its initially ...
" the animal.
Role in reproductive behavior
Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s of the PAG are excited by
endorphins and by
opiate
An opiate, in classical pharmacology, is a substance derived from opium. In more modern usage, the term ''opioid'' is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonis ...
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s. It also plays a role in
female
Female (Venus symbol, symbol: ♀) is the sex of an organism that produces the large non-motile ovum, ova (egg cells), the type of gamete (sex cell) that fuses with the Sperm, male gamete during sexual reproduction.
A female has larger gamet ...
copulatory behavior (see
lordosis behavior
Lordosis behavior (), also known as mammalian lordosis (Greek lordōsis, from ''lordos'' "bent backward") or presenting, is the naturally occurring body posture for sexual receptivity to copulation present in females of most mammals including rod ...
) via a pathway from the ventromedial nucleus of the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
Role in maternal behavior
The PAG may be specifically involved in human
maternal behavior. The PAG contains a high density of
vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
and
oxytocin
Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
receptors, and it has direct connections with the
orbitofrontal cortex
The orbitofrontal cortex (OFC) is a prefrontal cortex region in the frontal lobes of the brain which is involved in the cognitive process of decision-making. In non-human primates it consists of the association cortex areas Brodmann area 11, 12 ...
, which might mediate the role of the PAG in maternal love. The lateral orbitofrontal cortex is activated by pleasant visual, tactile, and olfactory stimuli. Its response depends on pleasantness rather than on intensity of stimulation. Here, its activity is likely to reflect one aspect of the pleasant emotions associated with motherly love.
Additional images
File:Gray678.png, Schematic representation of the chief ganglionic categories (I to V).
File:Gray711.png, Transverse section of mid-brain at level of inferior colliculi.
File:Gray712.png, Transverse section of mid-brain at level of superior colliculi.
File:Periaqueductal_MRI.PNG, MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
section of human mid-brain showing periaqueductal gray
See also
*
Rostral ventromedial medulla
The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata (myelencephalon). The rostral ventromedial medulla sends descending inhib ...
*
Emotion
Emotions are mental states brought on by neurophysiological changes, variously associated with thoughts, feelings, behavioral responses, and a degree of pleasure or displeasure. There is currently no scientific consensus on a definition. ...
References
External links
*
{{Authority control
Midbrain
Pain