The Role of Substance P in Arthritis

Nociception and Neurogenic Inflammation

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Identifying Substance P

Substance P was initially discovered in 1931, but its significance in the body took decades to unravel. By the 1950s, it was determined that substance P was a neurotransmitter. Nerve cells communicate through neurotransmitters. Substance P was found to function as the pain transmitter of the dorsal horn. The dorsal horn is composed of sensory neurons and is found on all spinal cord levels.

By the 1970s, the biochemical properties of substance P were revealed. Substance P was identified as a protein composed of a sequence of amino acids.

The Role of Substance P

Numerous animal and in vitro studies were conducted so that the role of substance P in the body could be better understood. Researchers found that substance P caused pain through a process known as nociception. A nociceptor is a sensory neuron or nerve cell that reacts to potentially damaging stimuli by signaling the spinal cord and brain. Nociception causes the perception of pain. It was also discovered that substance P has pro-inflammatory effects.

Substance P and its chief receptor, neurokinin-1 (NK-1) receptor, are present in the neurons located throughout the neuroaxis (the axis that runs through the brain and spinal cord). Those neurons play a role in pain, stress, and anxiety. Substance P is also present in the limbic system of the central nervous system, including the hypothalamus and amygdala.

These areas are linked to emotional behavior.

Aside from pain perception, stress, and anxiety, substance P has also been found to play a role in numerous other physiologic responses:

  • vomiting
  • defensive behavior
  • change in cardiovascular tone
  • stimulation of salivary secretion
  • smooth muscle contraction
  • vasodilation

    Substance P and Arthritis

    Researchers have studied the involvement of substance P in arthritis and inflammatory disease. For substance P to play a role in arthritis, the nervous system must be involved in the pathophysiology of arthritis. There must be sensory nerve innervation to the joint. Certain findings suggest that is the case:

    • Substance P was found in specific key locations.
    • Substance P is present in higher concentration in the synovial fluid of rheumatoid arthritis patients.
    • The number of substance P receptors is different in rheumatoid tissue.

    Levine et al. proposed that neural mechanisms may provide an explanation for certain prominent features of rheumatoid arthritis: specific joints are more likely to develop arthritis; specific joints develop more severe arthritis; and the pattern of joints affected by rheumatoid arthritis is bilateral and symmetrical. Lotz et al. discovered another possible role for substance P in arthritis. Lotz and his team demonstrated that substance P could stimulate synoviocytes (synovial cells) in rheumatoid arthritis.

    Substance P increased the release of prostaglandin and collagenase from synoviocytes. 

    Targeting Substance P

    Has investigating the role of substance P delivered a new treatment target for rheumatoid arthritis? Not exactly. But, researchers claim there is potential for an NK1 receptor antagonist (a blocker) to be developed as a treatment for rheumatoid arthritis. In the meantime:

    • Glucocorticoids can reduce inflammation that originates in nerve tissue by decreasing the expression of NK-1, while increasing production of an enzyme that causes the degradation of substance P. 
    • Topical capsaicin can deplete substance P from local nerve endings to relieve pain. According to rheumatologist, Scott J. Zashin, M.D., capsaicin can take 1 to 4 weeks to work. To maintain the benefit of pain relief, capsaicin must be re-applied according to directions.  


    Role of Substance P in Inflammatory Arthritis. Garret NE et al. Annals of the Rheumatic Diseases 1992;51: 1014-1018.

    Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis. Levine JD, Collier DH, Basbaum AI, Moskowitz MA, Helms CA. The Journal of Rheumatology. 1985, 12(3):406-411.

    Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis. Lotz M, Carson DA, Vaughan JH. Science. 1987 Feb 20;235(4791):893-5.

    A Role for Substance P in Arthritis? Keeble and Brain. Neuroscience Letters. Volume 361. Issues 1–3, 6 May 2004. Pages 176–179

    The Role of Substance P in Inflammatory Disease. O'Connor T et al. Journal of Cell Physiology. 2004 Nov;201(2)167-80.

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