Page 355 - ONLINE PROCEEDING BOOK WSAVA 2017
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the cell body. With increased activity along a nerve
 ber the cell body becomes very active, synthesizing proteins and receptors, packaging them and sending them long distances along axonal  laments to be placed at nerve terminals, the dorsal horn and along the axons themselves. Ion channel populations change dramatically during chronic pain states, and all of these changes begin with the cell body in the DRG. It is also very interesting to recognize that the DRG is the region in the CNS that is least protected by the blood-brain- barrier. Thus the cell body becomes privy to circulating proteins, drugs, in ammatory mediators and toxins that are excluded from the bulk of pain processing.
Lidocaine (IV route)
Anti-in ammatories (NSAID or steroid) Acetaminophen (centrally acting COX modi cation) Anti-epileptics (gabapentin, pregabalin, etc.)
Returning to the dorsal horn of the spinal cord, the  rst order neuron devolves the electrical signal from the painful stimulus into a chemical one. Keep in mind that ions still play a major role in this step, with calcium being required to release neurotransmitters into the cleft. The signal is carried across the cleft between  rst and second order neurons by diffusion of these proteins. The major players in passing this information across the synapse are glutamate and substance P. Many other proteins, receptors and ion channels contribute to the complexity of this process. When repeated stimulation occurs additional channels, proteins and receptors become active. These may serve to facilitate transfer of signals
or to dampen transfer of signals. I will discuss the most relevant details in the discussion about currently available therapies directed at this aspect of pain processing.
Adding to the complexity, recognize that there are likely more than just two nerve-endings at the synaptic cleft being stimulated in our discussion. The signal is likely to also pass to interneurons, rapid projecting neurons and glial receptors that live in the same immediate neighborhood. The glial system and other support cells (mast cells, resident macrophages, etc) have recently been recognized as potent and active contributors
to pain signaling. Likewise, interneurons can serve in inhibitory, excitatory and recruiting functions.
Narcotics (opioids) Serotonin/norepinephrine modi ers NMDA antagonists
Alpha-two modi ers
Cannabinoids
Centrally acting anti-in ammatories (NSAIDS, steroids, acetaminophen)
An Urban Experience
After neurotransmitters diffuse across the cleft they bind to speci c receptors (such as AMPA and NK1 respectively) which in turn initiate electrical depolarization of the second order neuron. This second order neuron, or projection neuron, will carry the signal up to the brain-stem. The spino-cervico-thalamic tract is one of the major paths for somatic pain signaling in domestic animals and it crosses midline in the cervical region- arriving in the thalamus
with minimal synaptic modi cation. The spinoreticular tract is the second important pathway for pain signaling, especially important in carrying deep or visceral pain.
It tends to undergo extensive branching and synaptic modi cation as it ascends both sides of the spinal cord. This difference in ascending tracts helps to explain some of the physiologic and pharmacological differences between somatic and visceral pain. Interestingly, the spinoreticular tract also sends some signals directly through the limbic system- giving a structural reason for the common experience that visceral pain lends a greater sense of misery than super cial somatic pain.
Spinally administered drugs
Once pain a pain signal has arrived in the thalamus
or reticular system it is distributed to a variety of regions in the cortex, limbic system, midbrain, etc. The nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis in the medulla receive signaling and provide descending inhibition utilizing serotonin and norepinepherine. The hypothalamus releases endorphin and initiates a cascade of opioid- dependent inhibitory mechanisms.
Narcotics (opioids) Serotonin/norepinephrine modi ers NMDA antagonists
Alpha-two modi ers
Cannabinoids
Anxiety modi ers (environment, sedatives)
Centrally acting anti-in ammatories (NSAIDS, steroids, acetaminophen)
Acupuncture, massage, exercise
The mechanistic explanation of pain signaling that
has emerged around the  rst synaptic transfer (dorsal horn of the spinal cord) does not translate easily to the complexity found in the CNS. Pain signals synapse in the limbic system, allowing emotional state and memory to affect processing. They synapse in regions that alter autonomic activity, thereby increasing or decreasing physiological functions, levels of consciousness, etc. The milieu of output from the CNS, is therefore less distinct. This is frustrating as a scientist, but perhaps more fascinating as a clinician as it allows entry of concepts such as ‘quality of life’ and ‘comfort’.
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