Neuroimmune interactions

Multiple pathophysiological changes occur at the site of an injury. These result from mutual neuroimmune interactions and contribute to plasticity at the peripheral terminals of sensory neurons (Stein 1995). In response to trauma, an inflammatory process develops quickly, characterized by the migration of polymorphonuclear leukocytes into the affected area in the early phase followed immediately afterwards by lymphocytes, macrophages, and monocytes. Products from cell breakdown (prostaglandins, protones), plasma leakage (bradykinin), and inflammatory cells (cytokines, histamine, serotonin) directly stimulate (bradykinin, protones) and/or indirectly sensitize (prostaglandins) primary afferent neurons. This results in a reduction of nociceptive thresholds of C and A primary afferent nerve endings (hyperalgesia). A subpopulation of these nociceptors ('silent nociceptors') which are unresponsive under normal conditions may be activated in inflammation, leading to an expansion of their peripheral receptive fields ( Schaible and GrubbJ^;?).

The primary afferent nerve ending itself contributes to these changes. It contains various neuropeptides such as substance P and CGRP. Under inflammatory conditions, the neuronal content of these peptides is upregulated and their axonal transport towards the peripheral nerve endings is increased. This upregulation is partially caused by nerve growth factor which is abundant in inflamed tissue. Substance P and CGRP are released into the injured tissue where they can modulate the secretion of mediators and cytokines from resident immune cells and may contribute to an increased inflammatory response. This closes the vicious cycle of mutually reinforcing effects between immune cells and primary afferent nerve terminals resulting in enhanced hyperalgesia and pain ( Schaibleand Grubb 1993).

Concurrently, however, counteractive endogenous mechanisms are being established to inhibit inflammatory pain at the site of the injury. These mechanisms are also based on an interaction between the immune and nervous systems. Opioid receptors are synthesized in dorsal root ganglia and present on peripheral sensory nerve fibers. Owing to an enhanced axonal transport towards peripheral nerve terminals, their number is upregulated during inflammation. When activated by exogenous opiates (morphine), these receptors can mediate potent analgesia, similar to the activation of opioid receptors within the central nervous system but without central side-effects (Stein 1995). In addition, injured tissue contains elevated concentrations of endogenous opioid peptides. These peptides (b-endorphin, enkephalins, dynorphin) are synthesized within resident lymphocytes, monocytes, and macrophages, and can be released by stressful stimuli. This release can be triggered by a paracrine action of endogenous corticotropin-releasing factor, which is abundantly expressed in inflamed tissue, or by exogenous corticotropin-releasing factor and interleukin 1b, resulting in potent inhibition of inflammatory pain ( SMn!995).

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