Abstract

The synovial tissue is innervated by nociceptive sensory nerve fibers and sympathetic postganglionic nerve fibers. While sensory nerve fibers have afferent (by transmitting pain to the CNS) and efferent functions (by local release of neuropeptides), sympathetic nerve fibers exert mainly efferent vasoregulatory, energy-regulating and immunomodulating roles. In synovial tissue of patients with rheumatoid arthritis (RA), the major proinflammatory neuropeptide of sensory nerve fibers is substance P, which is upregulated relative to anti-inflammatory calcitonin gene-regulated peptide (CGRP). In addition, sensory nerve fibers undergo a sprouting response leading to sensory hyperinnervation of RA synovial tissue. Removal of sensory nerve fibers exerts anti-inflammatory effects, and it is thought that this elimination is beneficial during hemiplegia, which can spare the paralytic limb from developing RA. Therapeutic neutralization of substance P was not successful, most probably due to vast receptor redundancy. Furthermore, the sensory nervous system undergoes a sensitization response (aggravation of pain and inflammation) in the synovial tissue, the dorsal root ganglion, the spinal cord, and more central in the brain. Chemical sympathectomy or suppression of adrenergic signaling significantly reduce inflammatory processes in the initial acute state of inflammation whereas the same procedures may increase inflammation at later stages. These findings indicate that the sympathetic nervous system supports the development of inflammation but can reduce inflammation at more chronic stages. During chronic inflammation, the density of sympathetic nerve fibers in synovial tissue is reduced but other tyrosine hydroxylase-positive cells secreting noradrenaline appear in the inflamed joint. In addition to local vascular effects in the joint, the sympathetic nervous system influences numerous immune processes in the joint and in lymphoid organs. Hence the net effect of the sympathetic nervous system on inflamed tissue results from local sympathetic effects in the joint as well as from sympathetic influences on major systemic immune processes and energy regulation. This lecture summarize the central aspects of the two nervous systems.