ascending pain pathways. What is the concept of peripheral and central sensitization in chronic pain syndromes.
Sensory fibers (nociceptor afferents) that transmit pain sensations innervate all the body tissues. There are two types of sensory fibers—myelinated A-delta (δ) and unmyelinated C fibers. These fibers have free nerve endings containing nociceptors that respond to noxious stimuli. There are specific nociceptors for mechanical, thermal, and chemical stimuli. Another receptor (polymodal receptor) responds to more than one stimulus and is only found on C fibers. Aδ fibers are rapidly conducting and respond mostly to mechanical and thermal stimuli. C fiber afferents conduct more slowly and produce perceptions of dull, aching, or burning pain.
These nociceptor afferents (first order neurons) enter the spinal cord via dorsal roots and terminate in the dorsal horn of the spinal cord. These afferents release excitatory neurotransmitters that activate second-order neurons. The Aδ sensory neurons mainly release glutamate that binds to the N-methyl-D-aspartate receptor on second-order neurons that cross the cord and ascend in the neospinothalamic (lateral spinothalamic) tract and terminate in the ventroposterior basal nuclei of the thalamus. From there, the neural input is relayed to the somatosensory cortex which is important for sensory discrimination, location, and anticipation of the pain. The C fiber sensory neurons release substance P and other neurotransmitters that stimulate second-order neurons in the dorsal horn of the spinal cord. Also located in this area are the wide dynamic range (WDR) neurons that are stimulated by both noxious and non-noxious stimuli transmitted from the periphery by C fibers with polymodal nociceptors. The second-order neurons including the WDR neurons ascend in the paleospinothalamic tracts that terminate in the thalamus (anterior spinothalamic tract), periaqueductal gray (PAG) and reticular formation/nuclei (spinoreticular tract), and the medullary and tectal areas
From the thalamus, PAG, and other gray matter areas, third-order neurons transmit to other areas of the brain and spinal cord. Spinothalamic projections facilitate nociceptive input to the insular cortex, which has interconnections with the amygdala, prefrontal cortex, and anterior cingulate cortex. These regions form a network involved in emotional, cognitive, and autonomic responses to pain. In addition, there are interconnections with the hypothalamus that are involved in stress and autonomic responses. Finally, stimulation of the PAG, hypothalamus, and other areas are important in activation of the descending analgesia pathway.
The concept of peripheral and central sensitization is important for an understanding of widespread chronic pain conditions such as FM. With continuous and prolonged noxious stimulation (e.g., whiplash injury), peripheral polymodal C fibers and nearby silent nociceptive neurons that were previously unresponsive to stimulation now become responsive. The nociceptors begin to initiate signals spontaneously so that non-noxious stimuli are now perceived as noxious due to lowered pain threshold (peripheral sensitization). The result of peripheral sensitization causes a greater and more persistent barrage of nerve impulses to the dorsal root of the spinal cord. Release of substance P by C fibers sensitizes second-order neurons, including WDR neurons, to neurotransmitters, such as glutamate. The enhanced and persistent glutamate effect on second-order neurons can result in physiologic changes in the nerves so they become hyperexcitable. This is called windup. These hyperexcitable second-order neurons transmit excessively to the brain areas described earlier, resulting in expanded receptive fields, increased interconnectivity, and increased blood flow to the stimulated areas. The ability to expand the receptive field is called neuroplasticity and occurs more easily in younger brains, which may explain why painful events early in life are particularly likely to trigger FM. Due to these physiologic changes, central sensitization occurs so that the individual feels pain at a lower threshold and with increased intensity.
