The periaqueductal gray (PAG), also known as the central gray, is a brain region that plays a critical role in autonomic function,

motivated Motivation is an internal state that propels individuals to engage in goal-directed behavior. It is often understood as a force that explains why people or animals initiate, continue, or terminate a certain behavior at a particular time. It i ...

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 Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

modulation. It has

enkephalin An enkephalin is a pentapeptide involved in regulating nociception (pain sensation) in the body. The enkephalins are termed endogenous ligands, as they are internally derived (and therefore endogenous) and bind as ligands to the body's opioid ...

-producing cells that suppress pain. The periaqueductal gray is the

gray matter Grey matter, or gray matter in American English, 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 ...

located around the

cerebral aqueduct The cerebral aqueduct (aqueduct of the midbrain, aqueduct of Sylvius, Sylvian aqueduct, mesencephalic duct) is a small, narrow tube connecting the third and fourth ventricles of the brain. The cerebral aqueduct is a midline structure that passe ...

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 uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

. It projects to the

nucleus raphe magnus The nucleus raphe magnus (NRM) is one of the seven raphe nuclei. It is situated in the pons in the brainstem, just rostral to the nucleus raphe obscurus. The NRM receives afferent stimuli from the enkephalinergic neurons of the periaqueductal ...

, and also contains descending autonomic tracts. The ascending pain and temperature fibers of the

spinothalamic tract The spinothalamic tract is a nerve tract in the anterolateral system in the spinal cord. This tract is an ascending sensory pathway to the thalamus. From the ventral posterolateral nucleus in the thalamus, sensory information is relayed upwar ...

send information to the PAG via the

spinomesencephalic pathway The spinomesencephalic pathway, spinomesencephalic tract or spino-quadrigeminal system of Mott, includes a number of ascending tracts in the spinal cord, including the spinotectal tract. The spinomesencephalic tract is one of the ascending tracts ...

(so-named because the fibers originate in the

spine Spine or spinal may refer to: Science Biology * Spinal column, also known as the backbone * Dendritic spine, a small membranous protrusion from a neuron's dendrite * Thorns, spines, and prickles, needle-like structures in plants * Spine (zoology), ...

and terminate in the PAG, in the

mesencephalon The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

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

-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT (

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

) released from the

raphe nuclei The raphe nuclei (, "seam") are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the ...

descends to the dorsal horn of the spinal cord where it forms excitatory connections with the

inhibitory interneuron An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

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 peptides), which bind to mu and

kappa opioid receptor Kappa (; uppercase Κ, lowercase κ or cursive ; , ''káppa'') is the tenth 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 of 20. It was d ...

s, respectively, on the axons of incoming C and A-delta fibers carrying pain signals from

nociceptor A nociceptor (; ) 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 sensation of pain to direct attention to the body part, ...

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 type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator. Substance P ...

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

ventral posterolateral nucleus The ventral posterolateral nucleus (VPL) is one of the subdivisions of the ventral posterior nucleus in the ventral nuclear group of the thalamus. It relays sensory information from the second-order neurons of the neospinothalamic tract and me ...

(VPL) of the thalamus. The nociceptive signal is thus inhibited before reaching the cortical areas that interpret the signal as pain, such as the

anterior cingulate In human brains, the anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex that resembles a "collar" surrounding the frontal part of the corpus callosum. It consists of Brodmann areas 24, 32, and 33. It is involved in c ...

. This is sometimes referred to as the

gate control theory of pain The gate control theory of pain asserts that non-painful input closes the nerve "gates" to painful input, which prevents pain sensation from traveling to the central nervous system. The gate control theory of pain describes how non-painful sensati ...

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. Notably, the anterior cingulate cortex is thought to be responsible for emotional responses to pain, including perceived social or emotional pain. Reducing nociceptive signaling to this area not only reduces overall pain signaling, but appears to also reduce sensitivity to pain. Furthermore, activation of mu-opioid receptors has been shown to provide an "analgesic" effect for emotional 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 ...

, and increases in blood pressure and muscle tonus. 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 un ...

, 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 animal training, training an animal agai ...

" the animal.

Role in reproductive behavior

Neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s of the PAG are excited by

endorphins Endorphins (contracted from endogenous morphine) are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogeno ...

and by

opiate An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

s. It also plays a role in

female An organism's sex is female ( symbol: ♀) if it produces the ovum (egg cell), the type of gamete (sex cell) that fuses with the male gamete (sperm cell) during sexual reproduction. A female has larger gametes than a male. Females and ...

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 ro ...

) via a pathway from the ventromedial nucleus of the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

Role in maternal behavior

The PAG may be specifically involved in human maternal behavior. The PAG contains a high density of

vasopressin Mammalian 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 ...

and

oxytocin Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...

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, 1 ...

, 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 generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

section of human mid-brain showing periaqueductal gray

References

External links

* {{Authority control Midbrain Pain