Regulation of neurotensin receptors : involvement in the control of pain

In this project, we are particularly interested in the involvement of neurotensin (NT) and its receptors (NTS1 and NTS2) in acute and tonic pain models. The results obtained in this study will allow us to assess whether and NTS1 and NTS2 receptors may represent potential targets for the treatment of persistent pain and perhaps reduce hyperalgesia and allodynia induced during chronic pain. To do so, we begun behavioral studies in Sprague-Dawley rats and mice invalidated for NTS1 or NTS2 genes in order to assess the antinociceptive effects of neurotensin analogues. These observations are correlated with immunohistochemical studies that aim to assess the distribution of NT receptors in the spinal cord and cellular and molecular studies to decipher signaling pathways.

Pain transmission is a phenomenon that can be altered in response to stress. We hypothesized that antinociceptive effects of neurotensin during stress response could be triggered by the activation of its receptor NTS2. We will try to answer the following questions: (1) what is the effect of prenatal stress on the distribution and expression of NTS2 receptor? (2) Does the stress induced during pregnancy alters nociceptive response induced by NT? If so, (3) do NTS2 receptor agonists or antagonists will affect the stress-induced analgesia phenomenon? (4) Is there a correlation between the nociceptive response to stress and ontogenesis of NTS2 receptor?

Given the involvement of NTS2 receptor in analgesic effects of NT at the spinal and central level, we hypothesize that NTS2 receptor could be an attractive therapeutic target for the treatment of chronic cancer pain. The project goal is therefore to examine the role of NTS2 receptor in a cancer pain model. We suggest, using rats as animal model to examine the consequences of injecting syngeneic neoplastic cells (osteosarcoma cells) in the marrow cavity of the femur, one hand on the painful behavior ( 1) and on the other hand on the expression and distribution of NTS2 receptors at the lumbar part of the spinal cord and DRGs (2).

We hypothesized that CCR2 participates to the pronociceptive effects of MCP-1 and might therefore be an attractive therapeutic target for the treatment of chronic inflammatory pain. Using Sprague-Dawley rats as an animal model, we suggest to examine, over a time period of 21 days, the effects of inhibiting the function of MCP-1 / CCR2 axis on the nociceptive behavior caused by the intraplantar injection of complete Freund’s adjuvant (CFA) in the hind paw of the animals.

Funding Agencies
  • Canadian Institutes of Health Research
  • Canada Research Chairs
  • NSERC
  • FRQ-S
  • FRQ-NT