Lecture 13: Spinal Cord and Pain

Mechanism of Descending Normal Pain

Experience a painful stimulus, the ascending pain pathways both anterior and lateral spinothalamic tracts communicate pain via first and second order nociceptor neurons. Second order decussate and ascend onward to brain stem, thalamus, and cortex. In brainstem there are periaqueductal gray (PAG) neurons. Stimulate cells in the raphe to secrete serotonin. Raphe cells send a descending projection down to the spinal cord where they form a synapse with enkephalin interneurons. Serotonin has an inhibitory effect on enkephalin cells; no enkephalin is released, so substance P continues to be released by the first order nociceptive cell. 1. PAG cells have stimulatory influence on SHT cells in raphe nucleus. 2. stimulate raphe SHT under normal conditions. 3. Get SHT release onto enkephalin cells. SHT has inhibitory effect on enkephalin cells so no enkephalin release. Substance P flows from DRG cell - you get pain.

Neospinalthalamic Tract

Later. Conducts signals of the exact location of the noxious stimulus. Quickly. Signal arrives in the lateral thalamus. In turn, third order nociceptive neurons in the lateral thalamus relay that signal on to the somatosensory cortex, where cortical connections allow for processing to figure out where the pain signal is emerging from in the body.

Nociceptive Specific Cells

Located superficial aspects of the dorsal horn (layers 1 and 2). Receive synaptic contacts from both a-delta and c-fiber cells. Preference of a-delta innervation. Only respond to noxious stimuli (tissue damage). Contribute to the neospinothalamic tract (lateral spinothalamic).

Lower Motor Neurons

Lower motor neurons reside in the ventral horn, send their axons out into the periphery to innervate muscles. They are the final common pathway through which the brain and spinal cord control muscles. All action depends on activating these lower motor neurons. Determines onset, coordination, duration, termination of all muscle activity. Receive and integrate a ton of signals from the brain and direct movement accordingly. Each lower motor neuron receives thousands of synapses. Integrating many signals can generate an action potential that travels down the axons, out the ventral root, can split and form branches around a particular area of muscle. The axon terminals innervating muscle fibers at the neuromuscular junction. As a result of this organization, when a lower motor neuron fires an AP, each of the muscle fibers it innervates is excited and therefore contracts.

Wide Dynamic Range Cells

Multireceptive. Located deeper in the dorsal horn of the spinal cord. Receive contacts from c-fibers and mechanoreceptor cells. Respond to multiple types of mechanical and thermal stimuli. Most of these axons decussate and ascend in anterior spinothalamic tract. Contribute to the paleospinothalamic tract (anterior spinothalamic).

Innervation Ratio

The number of fibers innervated by an axon. Low innervation ratio conceptualizes delicate muscles, finer movements. High innervation ratio conceptualizes large muscle groups, each motor neuron is potentially innervating hundreds of fibers to contract them simultaneously to produce a lot of force.

Descending Motor Pathways in the Spinal Cord

To produce rapid and coordinated movements, the brain and spinal cord have to continuously monitor the state of the muscles and positions of limbs in space (proprioception). Involves both ascending sensory and descending motor pathways. The origin for motor commands lies in the cerebral cortex; upper motor neurons originate descending tracts. Final common pathway for motor commands is the ventral horn of the spinal cord. Upper motor neurons in the motor cortex of the brain project axons down corticospinal tracts to contact lower motor neurons in the ventral horn of the spinal cord. Lower motor neuron axons exit the CNS and innervate the muscles. Lower motor neurons: cell bodies lie in the gray matter of the ventral horn, axons exit spinal cord via the ventral roots.

Mechanism of Descending Analgesia

Under the influence of brainstem opioid receptors. Can inhibit spinal function, then attenuate the pain. Brainstem neurons in PAG have opiate receptors. When endorphins and other opiates bind to the receptors, they inhibit the activation of PAG neurons. Functions to reduce activity of neurons in Raphe --> less serotonin release in spinal cord. Without serotonin in the spinal cord, there is no inhibition of enkephalin cells. Become active, release enkephalin, and those block Ca channels, substance P cannot be released. 1. opiates inhibit activity of PAG cells. 2. no stimulation of SHT cells in raphe. 3. no SHT release, so no inhibition of enkephalin cells. Enkephalin cells become active and release enkephalin. Blocks the release of substance P - no pain.

Pyramidal System

Upper motor neurons lie in the motor cortex of the brain. Pyramidal cells - betz cells. Pyramidal tracts: axons that leave upper motor neurons and the majority cross the midline at the decussation of the pyramids, thus are contralateral. Tracts descend in white matter and insert into ventral horn of spinal cord and innervate lower motor neurons. Lateral corticospinal tract.

Pain

When damage occurs a sequence of event occurs. Primary sensory nociceptive neurons located in the DRG have very specialized neurites projecting into the periphery that terminate in free nerve endings that conduct action potentials in response to noxious stimuli (tissue damage) toward the CNS. Pain originating in the PNS is based on excitation of nociceptive afferent fibers. Afferent fibers can be classified into two types: large myelinated a-delta fibers and smaller unmyelinated c-type fibers. Two opposing systems control pain: ascending nociceptor system and descending analgesia system.

Substance P

A (11 amino acid chain) peptide that is stored in vesicles and released from the sensory nerve fibers in response to damage as well as in response to endogenous signals that are released in response to damage. Secreted by free nerve endings in the periphery, it is also found in the dorsal horn. Specifically located within areas of c fiber and a-delta fiber synaptic termination. There is colocalization: overlap of SP and its receptor. Evidence that SP is a pain transmitter; reduced SP levels in rats caused severe losses in nocicpetion. In humans, pain insensitivity syndrome is caused by depletion of spinal SP. Damage --> endogenous chemicals --> substance P --> more endogenous chemicals --> more substance P. Ex: substance P causes serotonin to be released from platelets. Can act as a vasoconstrictor or dilator. It is also exciting nociceptors. Substance P is also controlling mast cell activation. Mast cells are a component cell of connective tissue that release histamines. Histamines also evokes the nerve to release more substance P.

Motor Unit

A single motor neuron and all the muscle fibers it innervates. Each branch of the lower motor neuron innervates a separate muscle fiber within the larger muscle.

Projection to Reticular Formation

Also a tract from the spinal cord. From dorsal horn to reticular formation of the medulla. Conveyed via the pons onto the medial thalamus as well. Is another way in which pain signals from the lower body reach the cerebral cortex, but importantly, it plays a role in descending analgesic pathways that help us modulate the sensation and perception of painful experiences.

Paleospinothalamic Tract

Anterior. Terminates in the medial nuclei of the thalamus. IN turn, third order thalamic neurons relay this wider dynamic, more informationally diverse signal, from the medial thalamus to the associational cortex. Here, the associational cortices, because of their myriad of multimodal inputs, signals that the associational cortices provide and respond to pain sensation and perception is one of affect and assessing the quality/meaning of the painful experience.

Nociception and Spinothalamic Tract

First order nociceptors enter into the spinal cord via the dorsal root; cell bodies are in the DRG. Pain signals are conveyed by unmyelinated type c fibers as a consequence more slowly; type a-delta also convey pain signals. Enter into the dorsal root. Terminate mainly in rexed laminae 1, 2 and 5 (marginal, gelatinosa, noxious/visceral afference). The second order nociceptor cells in the dorsal horn of the spinal cord are of two types: (1) nociceptive specific cells and (2) wide dynamic range cells (multireceptive). These cells originate and contribute to the neospinal thalamic and paleospinothalamic tracts respectively (lateral and anterior). If these second order nociceptors are receiving different inputs, it follows that the projections that they originate are going to be informationally unique as well. Nociceptive specific and wide dynamic range cells originate these two different pathways and tracts, which carry unique signals about painful stimuli. Those signals are conveyed to different nuclei in the thalamus.

Endorphins

In pituitary and brain. Comprised of 31 amino acids; peptides. Mediates the analgesic response.

Enkephalins

In spinal cord and adrenal gland. Smaller peptides (5 amino acids). Mediates the analgesic response. Ascending nociceptor afference arriving in the dorsal root to the dorsal horn of the spinal cord of the spinal cord. Co-localize with substance P (nociceptors) in the dorsal horn of the spinal cord. SP is sepcifically expressed in synaptic terminals of DRG cells. First order axon terminals synapse on second order nociceptive cells in the dorsal horn. Those decussate and enter into corresponding tracts. Enkephalin in synaptic terminals of enkephalin cells in the dorsal horn. Make axosynaptic synapses on substance P containing terminals in the dorsal horn. Axon terminals that originate from nociceptive first order neurons.

Upper Motor Neurons

Send two fiber bundles as part of the corticospinal tracts down either side of the cord (pyramidal and extrapyramidal tracts) to activate lower motor neurons.

Fibers of the Ascending Nociceptor System

Nociception is carried to the spinal cord by small unmyelinated fibers (c-fibers) and by small myelinated fibers (a-delta fibers). C and A-delta fibers terminate in superficial aspects of the dorsal horn of the spinal cord. More specifically they terminate in the dorsal portions of the dorsal horns, in the upper rexed laminae. C fibers preferentially project to the superficial lamina (layer 1: marginal, layer 2: substantial geltainosa). A-delta fibers also terminate more deeply in the dorsal horn of the spinal cord. C-fibers are smaller unmyelinated pain fibers, as a consequence of diameter and lack of myelination, signals communicated by these afferents are relatively slow. Because a-delta fibers are myelinated, they conduct impulses more rapidly. Pain fbers conduct relatively slowly and project diffusely. C and a-delta cells synapse immediately in the dorsal horn of the spinal cord onto secondary nociceptor cells -conveying pain information.

Pain and Monoamines

Normally, the DPMS elicit the release of monoamines, specifically norepinephrine and serotonin onto spinal circuits. These contribute to pain sensation. However, the release of these monoamines is under the influence of brainstem opioid receptors. Opioid receptors can inhibit spinal functions; in this, they allow for attenuation of pain signals. Thus, the DPMS involved endogenous opiates; enkephalins and endorphins.

Descending Pain Modulatory System (DPMS)

Pain sensation and perception can be modified by factors such as depression, anxiety, mood, attention, drugs. This regulates nociceptive processing, specifically in the dorsal horn of the spinal cord. Consequence: the DPMS affects how pain signals enters the brain. Brain stem component of the DPMS involves a number of nuclei. Electrical stimulation of a number of areas within the brainstem will render an animal analgesic giving pain "relief". Brain regions involved: periaqueductal gray (PAG), rostral ventromedial medulla (RVM, includes raphe nucleus), endogenous opiate like molecules mediate this analgesic response.

Mechanism of Enkephalin Action

Pain signal arrives via the first order nociceptive cell that has cell body in DRG. Pain is coming from the periphery and ascending in the spinal cord. Pain is signaled to the second order neuron via the neuropeptide susbtance P. When that nociceptor afferent is excited, the AP invades the presynaptic terminal and SP is released to produce an EPSP in the post synaptic second order cell in the dorsal horn. Enkephalins produce pain control (analgesia) pre-synaptically, by inhibiting the release of substance P into the spinal cord by nociceptor cells located in the DRG. Enkephalin cell originates the axogynaptic synapse which is a synapse with the first order nociceptor axon terminal. Enkephalin positive interneuron is releasing enkephalin specifically onto the presynaptic terminal of the first order nociceptor cell. Enkephalin blocks calcium channels in the presynaptic terminal --> prevents the release of NT --> no SP released.

Extrapyramidal System

Part of the motor system network which does not descend in the pyramids of the medulla. Rubro, reticulo, and vestibulospinal tracts. Play a significant role in the motor system network supporting involuntary actions.

Ascending Nociceptor Systems

Primary nociceptor cells in the DRG. Neurites projecting into the periphery. Axons inserting into the dorsal horn of spinal cord. Mechanical damage depolarizes peripheral neurites. Sending depolarizing signal to DRG neurons. Tissue damage occurs: cells release of histamine (H), bradykinin (BK), prostaglandin (PG) and serotonin (5HT) = inflammation. Spreads inflammation and nociceptor discharge to nearby cells. Cause tenderness or hyperalgesia. These endogenous chemicals that are released in response to damage enhance nociceptor excitability --> evokes positive feedback loop.

Nociceptors

Sensory neurons which originate fibers that convey info about tissue damage or potentially damaging stimuli as well as thermal stimuli. Likely transmitter in first-order nociceptors is substance P. Projections of nociceptors: first order nociceptor cells are in the DRG. Axons of first order nociceptor cells enter the spinal cord directly. May ascend or descend very briefly in lishauers tracts. Synapse immediately with a second order cell in the dorsal horn of the spinal cord. Axons of the second order cell decussate and then project to brainstem and synapse with third order cells in thalamus and reticular formation. Ascend in lateral white mater of cord. Ascend as part of the anterolateral projection. Known as the spinothalamic tract. Courses upward in the contralateral spinal cord through the medulla and pons to the thalamus and reticular formation. Third order somatosensory nociceptor neurons in the thalamus project into the primary somatosensory cortex. Signals from the lower body enter into the lumbar regions of the spinal cord; signals from the upper body enter into the levels of the cervical spinal cord. Regardless of level, the axons enter directly and synapse immediately to second order neurons.