00:03Pain typically starts when nerve endings called nociceptors are activated.
00:08These nociceptors are found throughout the body and are usually activated in response
00:12to damage to tissue close to the nerve endings.
00:16Nociceptors can detect a range of noxious stimuli, including mechanical pressure, hot
00:21or cold temperatures, and certain chemicals released from damaged tissue.
00:25When a nociceptor is activated, it generates an action potential that travels along the
00:30axon of a sensory neuron.
00:32The axons that conduct pain signals generally fall into two categories, A-delta fibers, which
00:38are thinly myelinated and transmit signals relatively quickly, and C-fibers, which are
00:43unmyelinated and conduct signals more slowly.
00:47The A-delta fibers are responsible for fast, sharp pain, which might occur at the time of
00:52an injury.
00:53The C-fibers convey slow, dull pain, which often follows the initial pain of the injury.
01:00The sensory neurons carrying these signals enter the spinal cord through the dorsal root
01:05and branch off into ascending and descending claterals that travel up or down the spinal
01:10cord for one or more segments in a collection of fibers known as Lissauer's tract, before
01:15synapsing in the dorsal horn, an area of gray matter in the spinal cord, where they release
01:20the neurotransmitter glutamate as well as neuropeptides such as substance P. These substances activate
01:26a second set of neurons, called second-order neurons, that cross over to the other side
01:31of the cord to ascend in the anterolateral portion of the spinal cord.
01:36Because of their location, the ascending pathways that carry pain and temperature along with some
01:40other sensations are referred to as the anterolateral system.
01:45The main pathway for pain in the anterolateral system is called the spinothalamic tract.
01:51The spinothalamic tract is involved in the awareness of painful stimuli and the recognition
01:56of where in the body the painful stimulus is occurring.
01:59Spinothalamic tract fibers travel up from the spinal cord to the ventral posterior lateral
02:04nucleus and other nuclei of the thalamus.
02:07There they synapse on neurons that carry pain information to the cerebral cortex.
02:13The primary destination for these neurons is the somatosensory cortex, which is the main
02:18processing area for touch and pain sensations.
02:22Processing of pain information in the somatosensory cortex helps to identify the general aspects
02:27of pain, such as the location, intensity, and quality of pain.
02:32But pain perception is not confined to the somatosensory cortex.
02:36Many other regions are also thought to be involved.
02:39For example, areas like the insular cortex and anterior cingulate cortex also contribute
02:45to pain perception in various ways, such as by generating emotional responses to pain.
02:52There are several other pathways included in the anterolateral system, and they are thought
02:56to play unique roles in pain.
02:58The spinal reticular tract, for example, consists of a subset of spinothalamic tract fibers that
03:04terminate in both the thalamus and the reticular formation of the brainstem.
03:08It is thought to play a role in poorly localized pain and may be important to changes in attention
03:13in response to pain.
03:15Another collection of fibers, called the spinomesencephalic tract, extends to the periaqueductal
03:21gray in the brainstem.
03:23Stimulation of the periaqueductal gray plays an important role in pain modulation, a process
03:29by which the brain can modify and potentially decrease pain signals.
03:34Scientists are still working to fully understand natural pain modulation, but studies have found
03:39that descending pathways to the spinal cord arise from several brainstem areas, such as
03:44the raphe nuclei and locus coeruleus.
03:48Neurons that extend from the periaqueductal gray make excitatory connections with neurons
03:53in these and other regions, and those neurons travel down to the dorsal horn of the spinal
03:57cord, where they form inhibitory connections with neurons that transmit pain information.
04:03Thus, when neurons in the periaqueductal gray are activated, they activate brainstem regions
04:08that then inhibit pain transmission in the spinal cord, although it should be noted that recent
04:13research suggests this circuit might be involved in the facilitation of pain as well.
04:19The periaqueductal gray can be activated by signals from various other brain regions, but
04:24it is also readily activated by endogenous opioids, which are substances produced by the body that
04:29can cause natural pain-relieving effects by binding to opioid receptors, the same receptors
04:34that opioid drugs like morphine bind to.
04:37There are three major types of endogenous opioids, enkephalins, endorphins, and dynorphins.
04:45Endogenous opioids can activate neurons in areas like the periaqueductal gray to cause pain
04:50relief, but they can bind to receptors in the spinal cord, inhibiting pain transmission there
04:55as well.
04:55Of course, regions that have a high number of opioid receptors that endogenous opioids can
05:00bind to are also regions that are susceptible to the actions of opioid drugs.
05:06Similarly, endogenous cannabinoid substances, called endocannabinoids, are thought to reduce
05:12pain by binding to cannabinoid receptors in regions such as the periaqueductal gray, receptors
05:17that cannabis can also bind to to cause pain relief.
05:22There are a variety of other factors that can influence the experience of pain, both increasing
05:26and decreasing it.
05:28When pain sensitivity is increased, we refer to it as hyperalgesia.
05:33This can occur through a process called sensitization, which can happen peripherally to nociceptors
05:38or centrally to neurons in the spinal cord.
05:41Both peripheral and central sensitization can result in a situation where stimuli that would
05:46not normally be perceived as painful are deemed painful.
05:50This response is known as allodynia.
05:54Peripheral sensitization begins when nociceptors are exposed to chemicals released from cells
05:59at the site of an injury.
06:01These chemicals come from both neurons and non-neuronal cells, such as mast cells, platelets, and macrophages.
06:08The chemical mixture includes substances like substance P, bradykinin, histamine, serotonin,
06:16ATP, and others.
06:19Most of these substances act on nociceptor ion channels and receptors, making them more responsive.
06:26While it is believed the purpose of this chemical signaling is to protect the injured area, promote
06:30healing, and guard against infection, the chemical mixture also increases pain signals coming from
06:36the injury.
06:39Central sensitization is a rapid increase in the excitability of neurons in the dorsal horn
06:43of the spinal cord following high levels of nociceptor activity.
06:48This heightened excitability lowers the threshold for pain, increasing pain sensitivity.
06:53There are several mechanisms by which this can be achieved.
06:57One short-lasting form involves increased neuron firing due to repeated stimulation of nociceptors,
07:02which can cause the perceived intensity of pain to increase temporarily.
07:07Longer-lasting sensitization resembles the type of long-term potentiation that underlies
07:12memory consolidation and can lead to long-term changes in pain sensitivity.
07:17Pain sensitivity typically returns to baseline after healing, but nerve or central pathway damage
07:22can cause lasting sensitization leading to neuropathic pain, which can be an intensely painful,
07:28chronic, and difficult-to-treat condition that can involve both allodynia and hyperalgesia.
07:35Neuropathic pain can occur in conditions that involve nerve damage, such as diabetes, shingles,
07:41multiple sclerosis, stroke, and trauma.
07:58Neuropathic painpowered muzus Warumware draPathic Menendom
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07:59Leopathic
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