Porth's Essentials of Pathophysiology, 4e

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Nervous System

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respond to all three types of stimuli (mechanical, thermal, and chemical). Mechanical stimuli can arise from intense pressure applied to skin or from the violent contraction or extreme stretch of a muscle. Extremes of both heat and cold can stimulate nociceptors. Chemical stimuli arise from a number of sources, including chemical mediators released from injured and inflamed tissues. These chemi- cal mediators produce their effects by directly stimulating nociceptors or sensitizing them to the effects of nocicep- tive stimuli; perpetuating the inflammatory responses that lead to the release of chemical agents that act as nociceptive stimuli; or inciting neurogenic reflexes that increase the response to nociceptive stimuli. For example, bradykinin, histamine, serotonin, and potassium activate and also sensitize nociceptors, resulting in the lowering of the activation threshold. This in turn results in a trans- mission of afferent signals to the dorsal horn and causes neurogenic inflammation. 8 Other chemical mediators act alone or in concert to sensitize nociceptors through other chemical agents such as prostaglandins. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in controlling pain because they block the enzyme needed for prostaglandin synthesis. Peripheral Pain Fibers. Two types of afferent fibers transmit pain signals from the free nerve endings into the CNS: myelinated A δ fibers and unmyelinated C fibers. 1,2 The larger A δ fibers have considerably greater conduction velocities, transmitting impulses at a rate of 10 to 30 m/second. The C fibers are the smallest of all peripheral nerve fibers; they transmit impulses at the rate of 0.5 to 2.5 m/second. Pain conducted by A δ fibers traditionally is called fast pain or first pain and typi- cally is elicited by mechanical or thermal stimuli. C-fiber pain often is described as slow-wave pain or second pain because it is slower in onset and longer in duration, con- tinuing to elicit pain for up to 80 hours. 9 It typically is incited by chemical stimuli or by persistent mechanical or thermal stimuli. The slow postexcitatory impulses generated in C fibers are now believed to be responsible for central sensitization to chronic pain. Nociceptive stimulation that activates C fibers can cause a response known as neurogenic inflammation that produces vasodilation and an increased release of chemical mediators to which nociceptors respond. This inflammatory process results in vasodilation and the leakage of proteins and fluids into the extracellular space around the terminal end of the nociceptor. As a result, there is increased activity of immune cells, which further contributes to the inflammatory process. 8 This mecha- nism is thought to be mediated by a dorsal root neuron reflex that produces retrograde transport and release of chemical mediators, which in turn causes increasing inflammation of peripheral tissues. This reflex can set up a vicious cycle, which has implications for persistent pain and hyperalgesia (excessive sensitivity to pain), a condition in which the second-order neurons are overly sensitive to low levels of noxious stimulation. The transmission of impulses between the periph- eral nociceptive neurons and dorsal horn neurons in the spinal cord is mediated by neurotransmitters released

from nerve endings of the nociceptive neurons. 10 Some of these neurotransmitters are amino acids (e.g., glutamate), others are amino acid derivatives (e.g., norepinephrine), and still others are low–molecular-weight peptides com- posed of two or more amino acids. The amino acid glu- tamate is a major excitatory neurotransmitter released from the central nerve endings of the nociceptive neu- rons. Substance P, a neuropeptide, also is released in the dorsal horn by C fibers in response to nociceptive stimulation. Substance P elicits slow excitatory poten- tials in dorsal horn neurons. Unlike glutamate, which confines its action to the immediate area of the synaptic terminal, some neuropeptides released in the dorsal horn can diffuse some distance because they are inactivated by reuptake mechanisms. This may help to explain the excitability and unlocalized nature of many persistently painful conditions. Neuropeptides such as substance P also appear to prolong and enhance the action of glu- tamate. If these neurotransmitters are released in large quantities or over extended periods, they can lead to secondary hyperalgesia. Spinal Cord Circuitry and Ascending Pathways On entering the spinal cord through the dorsal roots, the pain fibers bifurcate and ascend or descend one or two segments before synapsing with association neurons in the dorsal horn. From the dorsal horn, the axons of association projection neurons cross through the ante- rior commissure to the opposite side and then ascend upward in the previously described neospinothalamic and anterolateral pathways (Fig. 35-8). The faster-conducting fibers in the neospinotha- lamic tract are associated mainly with the transmission of sharp–fast pain information to the thalamus. In the thalamus, synapses are made and the pathway continues to the contralateral parietal somatosensory area to pro- vide the precise location of the pain. Typically, the pain is experienced as bright, sharp, or stabbing in nature. The paleospinothalamic tract is a slower-conducting, multisynaptic tract concerned with the diffuse, dull, aching, and unpleasant sensations that commonly are associated with chronic and visceral pain. Fibers of this system also travel up the contralateral (i.e., opposite) anterolateral pathway to terminate in several thalamic regions, including the intralateral nuclei, which project to the limbic system. These projections are associated with the emotional or affective–motivational aspects of pain. Spinoreticular fibers from this pathway project bilaterally to the reticular formation of the brain stem. This component of the paleospinothalamic system facili- tates avoidance reflexes at all levels. It also contributes to elevated levels of alertness and increased heart rate

and blood pressure that can occur with pain. Brain Centers and Pain Perception

Information from tissue injury is carried from the spinal cord to brain centers in the thalamus where the basic sen- sation of hurtfulness, or pain, occurs (see Fig. 35-8). In the neospinothalamic system, interconnections between the