The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

Alla Khodorova, Grant D. Nicol, Gary Strichartz

Research output: Contribution to journalArticle

9 Scopus citations


The p75 neurotrophin receptor (p75NTR) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the roles of the same effectors, and of the tropomyosin receptor kinase A (TrkA) receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar skin to thermal stimulation after local sub-cutaneous injection of NGF (500 ng) was measured by the latency for paw withdrawal (PWL) from a radiant heat source. PWL was reduced from baseline values at 0.5–22 h by ∼40% from that in naïve or vehicle-injected rats, and recovered to pre-injection levels by 48 h. Local pre-injection with a p75NTR blocking antibody did not affect the acute thermal hyperalgesia (0.5–3.5 h) but hastened its recovery so that it had reversed to baseline by 22 h. In addition, GW4869 (2 mM), an inhibitor of the neutral sphingomyelinase (nSMase) that is an enzyme in the p75NTR pathway, also failed to prevent thermal hyperalgesia. However, C2-ceramide, an analog of the ceramide produced by sphingomyelinase, did cause thermal hyperalgesia. Injection of an anti-TrkA antibody known to promote dimerization and activation of that receptor, independent of NGF, also caused thermal hyperalgesia, and prevented the further reduction of PWL from subsequently injected NGF. A non-specific inhibitor of tropomyosin receptor kinases, K252a, prevented thermal hyperalgesia from NGF, but not that from the anti-TrkA antibody. These findings suggest that the TrkA receptor has a predominant role in thermal hypersensitivity induced by NGF, while p75NTR and its pathway intermediates serve a modulatory role.

Original languageEnglish (US)
Pages (from-to)384-397
Number of pages14
StatePublished - Jan 6 2017



  • TRPV1
  • atypical PKC
  • hypersensitivity
  • neurotrophin
  • pain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this