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Keywords:

  • GDNF;
  • NGF;
  • SP;
  • spinal delivery;
  • spinal release

Abstract

The aim of this study was to investigate the effects of intrathecally delivered trophic molecules nerve growth factor (NGF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) on substance P (SP) release and content in the rat spinal cord and SP content in sciatic nerve. SP release was assayed with an in vitro dorsal roots-attached spinal cord preparation, in which the roots were stimulated at A- or C-fibre strength, and SP levels were measured by radioimmunoassay (RIA). NGF but not NT-3 and GDNF treatment caused a significant increase in basal SP outflow; NGF, NT-3 but not GDNF increased C-fibre stimulation-evoked SP release, and capsaicin superfusion-induced SP release. The increase in C-fibre stimulation-evoked SP release over basal outflow was greater in NGF- than NT-3-treated cords, and nociceptive threshold testing showed that intrathecal NGF, but not NT-3 or GDNF treatment was associated with thermal hyperalgesia. There was no detectable A-fibre stimulation-induced SP release from any group as well as no change in SP content in the sciatic nerve and spinal cord. Systemic treatment with the NGF-sequestering fusion protein trkA-IgG significantly inhibited electrically or capsaicin-evoked SP release without affecting basal outflow and SP content in spinal cord and sciatic nerve. These results suggest that: (i) NGF tonically regulates the central synaptic function of SP-containing primary afferents; (ii) increased SP-release from the spinal cord is not necessarily associated with behavioural hyperalgesia as in NT-3-treated rats there was increased SP release but no detectable hyperalgesia; and (iii) because A-fibre stimulation failed to increase SP release in any group, these neurotrophins are unlikely to be responsible for the de novo upregulation of SP in large afferents seen after peripheral inflammation or nerve injury.