Cellular prion protein protects from inflammatory and neuropathic pain

Abstract

Cellular prion protein (PrPC) inhibits N-Methyl-D-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 PrPC null mice show a reduced threshold for various pain behaviours.We compared nociceptive thresholds between wild type and PrPC 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 PrPC null mice exhibited an MK-801 sensitive decrease in the paw withdrawal threshold in response both mechanical and thermal stimuli. PrPC 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, PrPC 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 PrPC may already be in a state of tonic central sensitization. Altogether, our data indicate that PrPC 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 PrPC.

Figure 1

Mechanical and thermal withdrawal threshold of PrP^+/+ and PrP^-/- mice. Time course of basal mechanical (panel A) and thermal (panel B) nociceptive threshold of wild type or PrP^c null mice as a function of the age of the animal. (C) Effect of pretreatment of 3 months old mice with MK-801 (3 nmol/i.t.) on mechanical withdrawal threshold. Each point or column represents the mean ± S.E.M. (n = 5-6). *P < 0.05, **P < 0.01.

Figure 2

Nociceptive response of PrP^+/+ and PrP^-/- mice under acute stimulation. Nociceptive response of wild type or PrP^c null mice in the first (panel A) and second (panel B) phases of formalin-induced (0.7% or 1.25%) nociception. C, D Effect of pretreatment of animals with MK-801 (3 nmol/i.t.) for the first (panel C) and second (panel D) phases of the formalin response. E. Nociceptive responses of WT and null mice following intraplantar injection of glutamate. Each column represents the mean ± S.E.M. (n = 6-9). *P < 0.05, ***P < 0.001.

Figure 3

Nociceptive response of PrP^+/+ and PrP^-/- mice in response to NMDA treatment. (A) Nociceptive response of wild type or PrP^c null mice following intrathecal injection of NMDA (30 pmol/i.t. or 300 pmol/i.t.). Each column represents the mean + S.E.M. (n = 5-6). *P < 0.05. (B) Effect of MK-801 on the pain behaviour induced by intrathecal injection of NMDA (30 pmol). Each column represents the mean ± S.E.M. Control data (hatched bars) were obtained following i.t. injection of 5 μl PBS (i.e., the same route of delivery as for NMDA). NMDA data were obtained either following i.p. injection of 10 ml/kg PBS (black bars) or 0.005 mg/kg MK-801 (white bars). In this case, PBS serves as a control for MK-801. (n = 6-9). *P < 0.05, **P < 0.01.

Figure 4

Nociceptive response of PrP^+/+ and PrP^-/- mice under neuropathic pain conditions. Mechanical (panel A) and thermal (panel B) withdrawal threshold of wild type or PrP^c null mice after CCI-induced neuropathy. The control data were obtained from sham-operated animals. (C) Effect of pretreatment of animals with MK-801 (3 nmol/i.t.) on mechanical withdrawal threshold. Each point or column represents the mean ± S.E.M. (n = 6-12). *P < 0.05, **P < 0.01, ***P < 0.001.