| Summary: | <p>Abstract</p> <p>Cellular prion protein (PrP<sup>C</sup>) inhibits <it>N</it>-Methyl-<it>D</it>-Aspartate (NMDA) receptors. Since NMDA receptors play an important role in the transmission of pain signals in the dorsal horn of spinal cord, we thus wanted to determine if PrP<sup>C </sup>null mice show a reduced threshold for various pain behaviours.</p> <p>We compared nociceptive thresholds between wild type and PrP<sup>C </sup>null mice in models of inflammatory and neuropathic pain, in the presence and the absence of a NMDA receptor antagonist. 2-3 months old male PrP<sup>C </sup>null mice exhibited an MK-801 sensitive decrease in the paw withdrawal threshold in response both mechanical and thermal stimuli. PrP<sup>C </sup>null mice also exhibited significantly longer licking/biting time during both the first and second phases of formalin-induced inflammation of the paw, which was again prevented by treatment of the mice with MK-801, and responded more strongly to glutamate injection into the paw. Compared to wild type animals, PrP<sup>C </sup>null mice also exhibited a significantly greater nociceptive response (licking/biting) after intrathecal injection of NMDA. Sciatic nerve ligation resulted in MK-801 sensitive neuropathic pain in wild-type mice, but did not further augment the basal increase in pain behaviour observed in the null mice, suggesting that mice lacking PrP<sup>C </sup>may already be in a state of tonic central sensitization. Altogether, our data indicate that PrP<sup>C </sup>exerts a critical role in modulating nociceptive transmission at the spinal cord level, and fit with the concept of NMDA receptor hyperfunction in the absence of PrP<sup>C</sup>.</p>
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