visceral pain is radiating has a somatic dermatomal pattern, and is known as referred pain. Referred pain represents a convergence of noxious input from visceral afferents activating second-order cells that are normally responsive to somatic sensation and leads to a well-delineated somatic discomfort at sites adjacent to or distant from internal sites of irritation or injury.
When there is prolonged noxious stimulation, the nociceptors can become sensitized. Pain hypersensitivity presents when either the thresholds are lowered so that stimuli that would normally not produce pain now begin to (allodynia), or the responsiveness is increased and the noxious stimuli produce an exaggerated and prolonged pain (hyperalgesia). Sensitization can be peripheral and central.
Peripheral sensitization represents a reduction in threshold and an increase in responsiveness of the nociceptors from peripheral targets such as skin, muscle, joints, and the viscera in response to inflammatory chemicals or mediators such as adenosine triphosphate (ATP) or prostaglandin PGE2.
Inflammatory factors released as a direct result of tissue injury or peptides released from collaterals of activated nociceptive nerve terminals (e.g., calcitonin gene-related peptide [CGRP] and substance P) induce increased vascular permeability and escape of plasma proteins into the tissue leading to edema at the injury site (Fig. 3.3). Primary afferent peptides, neurotransmitters, injury products like prostaglandins, as well as infiltrating immune cells and blood products like bradykinin escape from the vasculature, they combine to make important contributions to inflammation and to the pain resulting from the injury. Activation of receptors on peripheral terminals of "pain fibers" can initiate action potentials. Endogenous prostaglandins, bradykinin, and cytokines have strong peripheral actions and can sensitize as well as excite nociceptors.
Hyperalgesia is an exacerbation of pain in response to sensations that normally would not be perceived as painful as a result of the damage of the nociceptors or of the peripheral nerves. Primary hyperalgesia occurs directly in the damaged tissues due to sensitization of peripheral nociceptors to thermal stimulation, whereas secondary hyperalgesia occurs in surrounding undamaged tissues due to sensitization within spinal cord and central nervous system (CNS) to mechanical stimulation (Fig. 3.4). Hyperalgesia is mediated by platelet-activating factor (PAF) that leads to an inflammatory response.
Allodynia is pain induced by a stimulus which does not normally provoke pain. Allodynia can be mechanical allodynia (pain in response to light touch/pressure) or thermal allodynia (pain from normally mild skin temperatures in the affected area). Allodynia is a result of neuronal sensitization both in the thalamus and in the dorsal horns. In the thalamus cysteine-cysteine chemokine ligand 21 (CCL21) induces production of prostaglandin E2 (PGE2) that can sensitize nociceptive neurons and lower their threshold to pain. In the dorsal horns of the spinal cord, tumor necrosis factor-alpha (TNF-alpha) increases the number of
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