Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

Neuroscience. 2016 Jun 2:324:390-8. doi: 10.1016/j.neuroscience.2016.03.032. Epub 2016 Mar 18.


We propose that the extracellular matrix (ECM) signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation in the rat hind paw. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A (PKA) and Src, but not protein kinase C (PKC), significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the ECM that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.

Keywords: CD44; extracellular matrix; hyaluronan; hyperalgesia; nociceptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrageenan / toxicity
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Extracellular Matrix / metabolism*
  • Hindlimb / physiopathology
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Inflammation / drug therapy
  • Inflammation / physiopathology
  • Male
  • Nociceptors / drug effects
  • Nociceptors / physiology*
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Rats, Sprague-Dawley
  • Touch


  • Hyaluronan Receptors
  • Carrageenan
  • Hyaluronic Acid
  • Proto-Oncogene Proteins pp60(c-src)
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C