Role of tachykinin 1 and 4 gene-derived neuropeptides and the neurokinin 1 receptor in adjuvant-induced chronic arthritis of the mouse

PLoS One. 2013 Apr 23;8(4):e61684. doi: 10.1371/journal.pone.0061684. Print 2013.


Objective: Substance P, encoded by the Tac1 gene, is involved in neurogenic inflammation and hyperalgesia via neurokinin 1 (NK1) receptor activation. Its non-neuronal counterpart, hemokinin-1, which is derived from the Tac4 gene, is also a potent NK1 agonist. Although hemokinin-1 has been described as a tachykinin of distinct origin and function compared to SP, its role in inflammatory and pain processes has not yet been elucidated in such detail. In this study, we analysed the involvement of tachykinins derived from the Tac1 and Tac4 genes, as well as the NK1 receptor in chronic arthritis of the mouse.

Methods: Complete Freund's Adjuvant was injected intraplantarly and into the tail of Tac1(-/-), Tac4(-/-), Tacr1(-/-) (NK1 receptor deficient) and Tac1(-/-/)Tac4(-/-) mice. Paw volume was measured by plethysmometry and mechanosensitivity using dynamic plantar aesthesiometry over a time period of 21 days. Semiquantitative histopathological scoring and ELISA measurement of IL-1β concentrations of the tibiotarsal joints were performed.

Results: Mechanical hyperalgesia was significantly reduced from day 11 in Tac4(-/-) and Tacr1(-/-) animals, while paw swelling was not altered in any strain. Inflammatory histopathological alterations (synovial swelling, leukocyte infiltration, cartilage destruction, bone damage) and IL-1β concentration in the joint homogenates were significantly smaller in Tac4(-/-) and Tac1(-/-/)Tac4(-/-) mice.

Conclusions: Hemokinin-1, but not substance P increases inflammation and hyperalgesia in the late phase of adjuvant-induced arthritis. While NK1 receptors mediate its antihyperalgesic actions, the involvement of another receptor in histopathological changes and IL-1β production is suggested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / genetics*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Edema / chemically induced
  • Edema / genetics*
  • Edema / metabolism
  • Edema / pathology
  • Freund's Adjuvant
  • Gene Expression Regulation
  • Hyperalgesia / chemically induced
  • Hyperalgesia / genetics*
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Inflammation
  • Interleukin-1beta / biosynthesis
  • Joints / metabolism*
  • Joints / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plethysmography
  • Protein Precursors / deficiency
  • Protein Precursors / genetics*
  • Receptors, Neurokinin-1 / deficiency
  • Receptors, Neurokinin-1 / genetics
  • Signal Transduction
  • Substance P / deficiency
  • Substance P / genetics*
  • Tachykinins / deficiency
  • Tachykinins / genetics*
  • Tarsus, Animal / metabolism*
  • Tarsus, Animal / pathology


  • Interleukin-1beta
  • Protein Precursors
  • Receptors, Neurokinin-1
  • Tac4 protein, mouse
  • Tachykinins
  • Substance P
  • Freund's Adjuvant