The descending control system, which regulates the transmission of nociceptive information, is of particular interest. This system is believed to suppress excessive pain in certain situations. For instance, it is well-known that individuals such as soldiers on the battlefield, accident victims, and athletes in competition often experience minimal or no pain at the moment of injury. However, pain may later develop and become intense. Although the pain control system is part of a broader centrifugal control system that modulates various forms of sensation, it is medically significant enough to be recognized as a distinct system known as the endogenous analgesia system.

Multiple centers in the brainstem, along with the pathways originating from these centers, contribute to the endogenous analgesia system. Stimulation in the midbrain (Fig. 7.9A, Models of descending control of ascending pain pathways) serves as an example. This stimulation plays a role in modulating (gating) the flow of pain information into the brain, which is conveyed through the spinothalamic tract (STT). The descending pathway, originating in the periaqueductal gray (PAG) and projecting via the rostroventromedial (RVM) medulla to the dorsal horn, acts to block the transmission of pain information at the level of the spinal cord. 

The standard model of descending pain control proposes that GABAergic interneurons in the PAG and RVM, which are tonically active, inhibit projection cells (note that the PAG has local GABAergic interneurons but also receives GABAergic terminals from other brain regions). Opioids are thought to inhibit these GABAergic interneurons, thereby disinhibiting the projection neurons. The increased activity of these projection neurons leads to the blocking of activation of STT cells by nociceptive dorsal root ganglion (DRG) cells.

Another model, known as the parallel inhibition-excitation model, suggests that both excitatory and inhibitory cells project from the PAG and RVM. In this model, the transmission of pain information would be influenced by a balance of excitatory and inhibitory activity in the descending pathways. It is important to note that the excitatory and inhibitory pathways are shown on opposite sides for clarity in Figure 7.9C.

Enkephalin (Enk), an endogenous opioid peptide, is released by many of the terminals in the descending pain modulation pathways. Enk is believed to have both pre- and postsynaptic sites of action. Its presynaptic action may prevent the release of substance P (SubP) from nociceptors. Figure 7.9D illustrates the potential presynaptic and postsynaptic sites of action of Enk.

Various inhibitory pathways also originate in the sensorimotor cortex, hypothalamus, and reticular formation.

The endogenous analgesia system can be further divided into two components: one that utilizes endogenous opioid peptides as neurotransmitters and another that does not. Endogenous opioids are neuropeptides that activate specific opiate receptors.
Of particular interest is the descending control system that regulates transmission of nociceptive information. This system presumably suppresses excessive pain under certain circumstances. For example, it is well known that soldiers on the battlefield, accident victims, and athletes in competition often feel little or no pain at the time a wound occurs or a bone is broken. At a later time, pain may develop and become severe. Although the descending regulatory system that controls pain is part of a more general centrifugal control system that modulates all forms of sensation, the pain control system is so important medically that it is distinguished as a special system called the endogenous analgesia system.
Several centers in the brainstem and pathways descending from these centers contribute to the endogenous analgesia system. For example, stimulation in the midbrain •Fig. 7.9 A, Modelsofdescendingcontrolofascendingpainpathways.A,Schematicshowingtheascendingnociceptivepathwaythatconveyspaininformationtothebrain,representedbythespinothalamictract(STT),andthedescendingpathwaythatmodulates(gates)theflowofinformationintoit.Thedescendingpathwaystartsintheperiaqueductalgray(PAG),whichprojectsviatherostroventromedial(RVM)medullatothedorsalhorn.ActivationofthePAGorRVMblockstransmissionofpaininformationatthespinalcordlevel.B,Thestandardmodelofdescendingcontrolofpainperception.TonicallyactiveGABAergicinterneuronsinthePAGandRVMinhibittheprojectioncells(notethatthePAGhaslocalGABAergicinterneuronsbutalsoreceivesGABAergicterminalsfromotherbrainregions,andbothmaybeinvolvedintonicallyinhibitingthePAGprojectioncells).OpioidsappeartoinhibittheGABAergicinterneurons,thusdisinhibitingtheprojectionneurons,whoseincreasedactivityleadstoblockingtheactivationofSTTcellsbynociceptivedorsalrootganglion(DRG)cells.C,Parallelinhibition-excitationmodel.SomestudiessuggestbothexcitatoryandinhibitorycellsprojectfromthePAGandtheRVM.Inthismodel,gatingoftransmissionofpaininformationwouldbeduetoabalanceoftheexcitatoryandinhibitoryactivityinthedescendingpathways.Notethattheexcitatoryandinhibitorypathwaysareshownonoppositesidesjustforclarity.D,Possiblepresynapticandpostsynapticsitesofactionofenkephalin(Enk).ManyoftheterminalsfromthedescendingpathwaysforpainmodulationreleasebothGABAandenkephalin(EnK),whichappearstohavebothpre-andpostsynapticsitesofaction.ThepresynapticactionmightpreventreleaseofsubstanceP(SubP.)fromnociceptors.(A-C,RedrawnfromLauBK,VaughanCW.Curr Opin Neurobiol 2014;29:159.D,RedrawnfromHenryJL.In:PorterR,O’ConnorM[eds]:CibaFoundationSymposium91.London:Pitman;1982.) periaqueductal gray, locus coeruleus, or medullary raphe nuclei inhibits nociceptive neurons at the spinal cord and brainstem level, including spinothalamic and trigeminothalamic tract cells (
Fig. 7.9A-C ). Other inhibitory pathways originate in the sensorimotor cortex, hypothalamus, and reticular formation.
The endogenous analgesia system can be subdivided into two components: one component uses endogenous opioid peptides as neurotransmitters and the other does not. Endogenous opioids are neuropeptides that activate one of several types of opiate receptors. Some of the endogenous