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Cellular prion protein protects from inflammatory and neuropathic pain


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.


The dorsal horn of spinal cord is an important site for pain transmission and modulation of incoming nociceptive information arriving from peripheral nociceptors [1, 2]. Glutamate is the key neurotransmitter released by the primary afferent fibers [3, 4] and plays an important role in nociceptor sensitization and in the modulation of allodynia [5]. Glutamate receptors (GluRs) such as N-methyl-D-aspartate (NMDA) receptors contribute in various ways to pain induction, transmission and control [57]. Consequently, NMDA receptor inhibitors exhibit antinociceptive and analgesic effects in rodents [8, 9] as well in humans [10], however, their clinical use for the treatment of pain has been hampered by their CNS side-effects [11, 12]. For this reason, strategies such as src interfering peptides have been proposed as ways to interfere with NMDAR hyperactivity in the pain pathway without affecting basal NMDA receptor function [13].

NMDA receptors are regulated by a plethora of cellular signaling pathways that could potentially be targeted for therapeutic intervetion [14]. Along these lines, our laboratory has recently shown [15] that NMDA receptor activity in mouse hippocampal neurons is regulated by cellular prion protein (PrPc). Specifically, NMDA receptors expressed in mice lacking PrPC show slowed current decay kinetics, and spontaneous synaptic NMDA currents in pyramidal neurons displayed increased current amplitude [15]. We subsequently showed that PrPC protects from depressive like behavior by tonically inhibiting NMDA receptor activity [16], thus suggesting that the altered NMDA currents in PrPC null mice are associated with a clear behavioral phenotype. Given the important role of NMDA receptors in the afferent pain pathway, we hypothesized that absence of PrPC may give rise to pain hypersensitivity. Here, we show that PrPC null mice exhibit a decreased nociceptive threshold, both under basal conditions, as well as in models of inflammatory and neuropathic pain. These effects were reversed by treatment of the animals with the NMDA receptor antagonist MK-801, thus implicating NMDA receptor dysregulation in the observed pain phenotype.


Mechanical and thermal withdrawal threshold of PrP+/+ and PrP-/- mice

To determine if PrPC plays a role in the transmission of pain signals, we compared nociception in wild type and PrPC null mice. Paw withdrawal thresholds in response to mechanical and thermal stimuli were measured using the Dynamic Plantar Aesthesiometer (DPA) and Plantar Test devices, respectively. As shown in Figure 1, a blinded time-course analysis showed that PrPC null mice exhibit significantly decreased mechanical and thermal withdrawal thresholds when compared to the wild-type group. Specifically, mechanical thresholds were significantly different in 2 month old animals (Figure 1A) whereas differences in thermal threshold appeared became statistically significant at an age of 3 months (Figure 1B). These differences were then maintained up to an age of 5 months, after which point the experiment was terminated. To ascertain whether this effect was mediated by spinal NMDA receptor hyperfunction, we intrathecally (i.t.) delivered 3 nmol of the NMDA receptor blocker MK-801 10 minutes prior to assessing mechanical withdrawal threshold. As shown in Figure 1C, MK-801 reversed the decreased mechanical withdrawal threshold of PrPC null mice. Two-way ANOVA revealed a significant difference of genotype [F(2,57) = 5.6 P < 0.05] and genotype X-treatment interaction [F(1,43 = 5.5 P < 0.05)]. Altogether, these data indicate that the PrPC inhibits nociceptive signalling through an NMDA receptor dependent mechanism.

Figure 1
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 PrPc 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.

Nociceptive response of PrP+/+ and PrP-/- mice under acute stimulation

Next we used the formalin test to determine if PrPC null mice display increased sensitivity to acute nociceptive stimulation. As shown in Figure 2, PrPC null mice exhibited significantly elevated licking/biting time in both the first (Figure 2A) and second (Figure 2B) phases of nociception induced by formalin (0.7% or 1.25%). Treatment of mice with MK-801 (3 nmol/i.t., 10 min prior to testing) resulted in a significant reduction of the nociceptive behaviour of PrPC-/- null mice for both the first (Figure 2C) and second (Figure 2D) phases of formalin-induced nociception. Two-way ANOVA revealed a significant difference of genotype [F(2,31) = 3.4, P < 0.05] and genotype X-treatment interaction [F(6,52) = 3.4, P < 0.05)] for the earlier (first) phase, and for the second phase (genotype [F(11,80) = 4.3, P < 0.05] and genotype X-treatment interaction [F(16,35) = 3.4, P < 0.001)]).

Figure 2
figure 2

Nociceptive response of PrP+/+ and PrP-/- mice under acute stimulation. Nociceptive response of wild type or PrPc 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.

We also directly injected glutamate (3 μmol or 10 μmol) into the paws of wild type and null mice, and determined the time that the animals spent licking and biting over a 15 minute time course. As shown in Figure 2E, the higher dose of glutamate resulted in a significantly greater increase in response time compared to wild type animals.

Nociceptive response of PrP+/+ and PrP-/- mice in response to NMDA treatment

To further investigate the involvement of spinal NMDA receptors in the decreased nociceptive threshold of PrPC null mice we directly activated these receptors via i.t. NMDA injection. As shown in Figure 3A, PrPC-/- mice exhibited a significantly higher nociceptive response (licking/biting) induced by different concentrations of intrathecally delivered NMDA. Interestingly, intrathecal injection of the lower dose of NMDA (30 pmol), which did not appear to affect wild-type mice, increased licking/biting time in PrPC-/- null mice. These data suggest that hyperactivity of spinal NMDA receptors of PrPC null mice may account for the decreased nociceptive sensitivity observed for those animals. As expected, treatment of animals with MK-801 (0.005 mg/kg, i.p., 30 minutes prior) prevented the effects of NMDA (Figure 3B).

Figure 3
figure 3

Nociceptive response of PrP+/+ and PrP-/- mice in response to NMDA treatment. (A) Nociceptive response of wild type or PrPc 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.

Nociceptive response of PrP+/+ and PrP-/- mice under neuropathic pain

To determine if PrPC modulates pain signalling under neuropathic conditions, we examined the response of wild type and null mice after sciatic nerve ligation (Chronic Constriction Injury-CCI). As shown in Figure 4, sciatic nerve ligation triggered decrease mechanical (Figure 4A) and thermal (Figure 4B) withdrawal thresholds in wild-type mice. Strikingly, this treatment did not further augment the already increased sensitivity of null mice to thermal and mechanical stimuli, as if PrPC-/- mice behave as if they were tonically neuropathic. Moreover, treatment with MK-801 (3 nmol/i.t.) completely reversed mechanical allodynia induced by CCI in wild type mice and at least partially reversed the reduced mechanical threshold in nerve ligated PrPC null mice (Figure 4C). A three-way analysis of variance revealed a statistical difference between genotype [F(3,4) = 9.13, P < 0.05], genotype X-treatment interaction [F(1,07) = 4.7, P < 0.01] and genotype × treatment × nerve injured interactions [F(1,75) = 11.4, P < 0.05].

Figure 4
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 PrPc 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.


It is well established that glutamate is involved in nociceptive processing in the spinal cord in both normal conditions and under certain pathological nociceptive processes [4, 11, 17] with NMDA receptors being the a key player in the binding of glutamate and activation of postsynaptic responses [18]. Under conditions of neuropathic pain, NMDA receptors are upregulated to mediate sensitization in second order neurons give rise to a phenomenon termed "wind up" [1922] leading to allodynia and hyperalgesia [5]. Consequently, NMDA receptor antagonists have been known to decrease neuronal hyperexitability and reduce pain, and the efficacy of several NMDA receptor antagonists has been investigated in preclinical [8, 9, 23] and clinical pain studies [10]. Conversely, processes that augment NMDA receptor function would be expected to be pronociceptive.

We have recently shown that PrPC physically interacts with NMDA receptors to inhibit NMDA receptor activity in the brain [15]. The absence of PrPC resulted in increased amplitudes and durations of synaptic NMDA currents [15] whereas AMPA receptors were unaffected [24]. The data presented here are consistent with a similar NMDA receptor hyperfunction in the afferent pain pathway. Mice lacking PrPc displayed increased nociceptive responses in thermal and mechanical tests, and showed an increased susceptibility to the development of inflammatory pain. Of note, an intrathecal dose of NMDA (30 pmol/i.t.), which does not induce in wild-type animals any pain behaviour per se, produced nociceptive behaviour in PrPC null mice that was comparable to that exhibited by wild-type animals injected with a 10 fold higher dose of NMDA (300 pmol/i.t.). These data fit with NMDA receptor hyperactivity, and suggest that PrPC null mice behave as if they are in a basal neuropathic pain state.

It is well established that nociceptive behaviour observed during first phase of formalin pain is a result of the direct chemical activation of peripheral nociceptors and by the release of local glutamate by the primary afferent, whereas the second phase results from central sensitization of dorsal horn neurons induced by primary afferent activity and peripheral inflammatory response [25]. However, the nociception caused by intraplnatar ( injection of glutamate involves peripheral, spinal and supraspinal sites of action and is greatly mediated by both NMDA and non-NMDA receptors as well as by the release of nitric oxide [26]. Furthermore, it is also mediated by capsaicin-sensitive fibres and by release of neurokinins from sensory neurons that activate NK2 and B1 receptors [27]. NMDA receptor antagonists are effective in attenuating both phases of the nociception induced by formalin in rodents when delivered systemically [28, 29] or spinally [30, 31]. Moreover, NMDA receptor inhibitors reduced windup in dorsal horn neurons in animals with peripheral nerve injury [3234], and NMDA receptor inhibition may impair wind-up in spinal neurons that relay C fiber input to the primary somatosensory cortex [35]. Our data showing sensitivity of the all of the observed PrPC null mouse pain phenotypes to NMDA receptor blockers thus fit with these previous studies. Also in agreement with our data are results from Meotti and co-workers [36] showing that PrPC null mice exhibited higher number of abdominal constrictions following intraperitoneal acetic acid injection when compared to wild-type mice. On the other hand, the same study showed that PrPC null mice appeared to exhibit less pain in the tail-flick test, and had no difference in latency response in the hot-plate test, in contrast with our findings.

Although much attention has been focused on the infectious (misfolded) scrapie form of PrPC (termed PrPSc) it is becoming increasingly evident that normal PrPC plays an important role in the normal physiology of the nervous system [37]. This includes neuroprotection [15, 38] protection from epileptic seizures [39, 40] and from development of depressive like behaviour [16] all of which have been linked to NMDA receptors. Our findings showing increased pain in PrPC null mice fit with the concept of PrPC playing a beneficial physiological role. It is widely recognized that misfolding of PrPC into a β-sheet rich infectious prion mediates severe neurological phenotypes, such as Creutzfeldt-Jakob disease (CJD) and variant CJD [4143]. In these disorders, normal PrPC is progressively converted into infectious prions, which then form plaques and cause severe neurodegeneration, ultimately leading to death. It is possible that the conversion of normal PrPC results in altered NMDA receptor currents in these patients, either by a reduction in the levels of normal PrPC, or by binding of misfolded PrPSc to the receptor complex. Such a mechanism may indeed fit with data showing that neuronal cultures infected with PrPSc are protected from cell death by NMDA receptor blockers [44]. In this context, it is interesting to note that a substantial fraction of new variant CJD patients show increased pain sensitivity [45] including limb pain [46]. Furthermore, there is a case report of a woman who developed vulvodynia despite normal vulvo-vaginal examination, and this patient was subsequently diagnosed with CJD [47]. While it is unknown as to whether this is due to augmentation of spinal NMDA receptor function in these patients due to compromised PrPC regulation of the receptors, such a mechanism would be consistent with our observations in mice.


In summary, our data indentify PrPC as an important negative regulator of pain signalling. Considering that PrPC physically interacts with the receptor complex to depress current amplitude, it may perhaps be possible to mimic this inhibition with small organic molecules interacting at the PrPC interaction site on the receptor.

Materials and methods


All experiments were conducted following the protocol approved by the Institutional Animal Care and Use Committee (protocol #M09100) and all efforts were made to minimize animal suffering. Unless stated otherwise, 10 week old male mice (C57BL/6J wild type and PrP null weighing 25-30 g) were used. Animals were housed at a maximum of five per cage (30 × 20 × 15 cm) with food and water ad libitum. They were kept in 12 h light/dark cycles (lights on at 7:00 a.m.) at a temperature of 23 ± 1°C. All manipulations were carried out between 11.00 am and 3:00 pm. Different cohorts of mice were used for each test and each mouse was used only once. The observer was blind to the experimental conditions in the experiment examining the age dependence of the pain phenotype. Mice with a targeted disruption of the prion gene (PrP) of the Zürich 1 strain [48] were obtained from the European Mouse Mutant Archive (EM:0158; European Mouse Mutant Archive, Rome) and out-bred to generate PrP-/- (PrP-null) littermates used in the experiments. Genotyping was performed by gel electrophoresis of PCR products obtained from genomic DNA that was isolated from tail samples. Primers and PCR parameters were similar to those used previously [48].

Drugs and treatment

The following drugs were used in the study: L-glutamic acid hydrochloride, MK-801, N-methyl-D-aspartatic acid, Formaldehyde (Sigma Chemical Company, St. Louis, MO, USA). All drugs were dissolved in PBS. When drugs were delivered by the intraperitoneal (i.p.) route, a constant volume of 10 ml/kg body weight was injected. When drugs were administered by the intrathecal (i.t.) route, volumes of 5 μl were injected. Appropriate vehicle-treated groups were also assessed simultaneously. The choice of the doses of each drug was based on preliminary experiments in our laboratory.

Formalin test

The formalin test is a widely used model that allows us to evaluate two different types of pain: neurogenic pain is caused by direct activation of nociceptive nerve terminals, while the inflammatory pain phase is mediated by a combination of peripheral input and spinal cord sensitization [4951]. Animals received 20 μl of different concentrations of formalin solution (1.25% or 2.5%) made up in PBS injected intraplantarly ( in the ventral surface of the right hindpaw. We observed animals individually from 0-5 min (neurogenic phase) and 15-30 min (inflammatory phase). Following injection of formalin, the animals were immediately placed individually in observation chambers and the time spent licking or biting the injected paw was recorded with a chronometer and considered as nociceptive response. In experiemnts involving MK-801, mice were treated by intrathecal delivery 10 minutes prior to formalin injection (1.25%) at a dose of 3 nmol.

Intraplantar glutamate injection

The procedure used was similar to that described previously [26]. Briefly, a volume of 20 μl of glutamate (3 nmol/paw or 10 nmol/paw prepared in PBS) was injected into the ventral surface of the right hindpaw. Animals were observed individually for 15 min following glutamate injection. The amount of time spent licking the injected paw was recorded with a chronometer and was considered as nociceptive response.

Intrathecal NMDA injection

To directly investigate the role of spinal glutamate receptors in the nociceptive behaviour observed for PrPc knockout mice, we compared the nociceptive behavior of wild-type and PrPc knockout mice after a single intrathecal injection of NMDA. Animals received an i.t. injection of 5 μl of NMDA solution. Injections were given to non-anaesthetized animals using the method described by Hylden and Wilcox [52]. Briefly, animals were restrained manually and a 30-gauge needle attached to a 25-μl microsyringe was inserted through the skin and between the vertebrae into the subdural space of the L5-L6 spinal segments. NMDA injections (30 pmol or 300 pmol) were given over a period of 5 seconds. The amount of time that animals spent biting or licking their hind paws, tail or abdomen was determined with a chronometer and considered as nociceptive response. In experiments involving MK-801, mice were treated by intraperitoneal delivery 30 minutes prior to NMDA injection at a dose of 30 pmol/site.

Chronic constriction injury (CCI)-induced neuropathy

For neuropathic pain, we used a sciatic nerve injury model according to the method described by Bennett and Xie [53] with minor modifications. Briefly, mice were anaesthetized (isoflurane 5% indution, 2.5% maintenence) and the right sciatic nerve was exposed at the level of the thigh by blunt dissection through the biceps femoris. Proximal to the sciatic nerve trifurcation, about 12 mm of nerve was freed of adhering tissue and 3 loose ligatures (silk suture 6-0) were loosely tied around it with about 1 mm spacing so that the epineural circulation was preserved. In sham-operated rats, the nerve was exposed but not injuried. Mechanical and thermal withdrawal thresholds were determined 3 days after surgery. In another series of experiments, PrPC null mice received MK-801 (3 pmol/i.t.) and mechanical withdrawal threshold was evaluated 10 min after drug delivery.

Mechanical withdrawal threshold

To assess changes in sensation or in the development of mechanical allodynia, sensitivity to tactile stimulation was measured using the DPA (Ugo Basile, Varese, Italy). Animals were placed individually in a small enclosed testing arena (20 cm × 18.5 cm × 13 cm, length × width × height) with a wire mesh floor for 60 min. The DPA device was positioned beneath the animal, so that the filament was directly under the plantar surface of the foot to be tested. Each paw was tested three times per session. For experiment 1, the same cohort of both wild-type and PrPC null mice were tested at age 1, 2, 3, 4 and 5 months. For neuropathic pain, testing was performed on the ispsilateral (ligated) paw before ligation (day 0) and then on the 3rd day after ligation.

Thermal withdrawal threshold

Thermal hyperalgesia was examined by measuring the latency to withdrawal of the hind paws from a focused beam of radiant heat applied to the plantar surface using a Plantar Test apparatus (Ugo Basile). Three trials each for the right hind paws were performed and for each reading, the apparatus was set at a cut-off time of 20 s. As with mechanical pain testing, the same cohorts of either wild-type or PrPC null mice were used at 1, 2, 3, 4 and 5 months. Thermal withdrawal threshold was tested 1 day after they were used for mechanical testing. For neuropathic pain, testing was performed on the ispsilateral (ligated) paw before ligation (day 0) and then on the 4th day after nerve injury.

Statistical analysis

Data were presented as means ± SEM and evaluated by t-tests, two-way or three-way analysis of variance (ANOVA) followed by Tukey test when appropriate. A value of P < 0.05 was considered to be significant.


  1. Yaksh TL: Regulation of spinal nociceptive processing: where we went when we wandered onto the path marked by the gate. Pain 1999, 6: 149–152.

    Article  Google Scholar 

  2. Hill RG: Molecular basis for the perception of pain. Neuroscientist 2001, 7: 282–292. 10.1177/107385840100700405

    Article  CAS  PubMed  Google Scholar 

  3. Jackson DL, Graff CB, Richardson JD, Hargreaves KM: Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol 1995, 284: 321–325. 10.1016/0014-2999(95)00449-U

    Article  CAS  PubMed  Google Scholar 

  4. Larsson M: Ionotropic glutamate receptors in spinal nociceptive processing. Mol Neurobiol 2009, 40: 260–288. 10.1007/s12035-009-8086-8

    Article  CAS  PubMed  Google Scholar 

  5. Minami T, Matsumura S, Okuda-Ashitaka E, Shimamoto K, Sakimura K, Mishina M, Mori H, Ito S: Characterization of the glutamatergic system for induction and maintenance of allodynia. Brain Res 2001, 895: 178–185. 10.1016/S0006-8993(01)02069-8

    Article  CAS  PubMed  Google Scholar 

  6. Carlton SM, Coggeshall RE: Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res 1999, 820: 63–70. 10.1016/S0006-8993(98)01328-6

    Article  CAS  PubMed  Google Scholar 

  7. Nakanishi O, Ishikawa T, Imamura Y: Modulation of formalin-evoked hyperalgesia by intrathecal N-type Ca channel and protein kinase C inhibitor in the rat. Cell Mol Neurobiol 1999, 19: 191–197. 10.1023/A:1006937209676

    Article  CAS  PubMed  Google Scholar 

  8. Berrino L, Oliva P, Massimo F, Aurilio C, Maione S, Grella A, Rossi F: Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test. Eur J Pain 2003, 7: 131–137. 10.1016/S1090-3801(02)00086-1

    Article  CAS  PubMed  Google Scholar 

  9. Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, Rondelli I, Chamiot-Clerc P, Simonato M, Barbieri M: Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003, 306: 804–814. 10.1124/jpet.103.050039

    Article  CAS  PubMed  Google Scholar 

  10. Wiech K, Kiefer RT, Töpfner S, Preissl H, Braun C, Unertl K, Flor H, Birbaumer N: A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004, 98: 408–413.

    Article  CAS  PubMed  Google Scholar 

  11. Chizh BA: Novel approaches to targeting glutamate receptors for the treatment of chronic pain. Amino Acids 2002, 23: 169–176. 10.1007/s00726-001-0124-4

    Article  CAS  PubMed  Google Scholar 

  12. Millan MJ: The induction of pain: an integrative review. Prog Neurobiol 1999, 57: 1–164. 10.1016/S0301-0082(98)00048-3

    Article  CAS  PubMed  Google Scholar 

  13. Yu XM, Askalan R, Keil GJ, Salter MW: NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 1997, 275: 674–678. 10.1126/science.275.5300.674

    Article  CAS  PubMed  Google Scholar 

  14. Gladding CM, Raymond LA: Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci, in press.

  15. Khosravani H, Zhang Y, Tsutsui S, Hameed S, Altier C, Hamid J, Chen L, Villemaire M, Ali Z, Jirik FR, Zamponi GW: Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J Cell Biol 2008, 181: 551–565. 10.1083/jcb.200711002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Gadotti VM, Bonfield SP, Zamponi GW: Depressive-like behaviour of mice lacking cellular prion protein. Behav Brain Res, in press.

  17. Latremoliere A, Woolf CJ: Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009, 10: 895–926. 10.1016/j.jpain.2009.06.012

    Article  PubMed Central  PubMed  Google Scholar 

  18. Woolf CJ, Salter MW: Neuronal plasticity: Increasing the gain in pain. Science 2000, 288: 1765–1769. 10.1126/science.288.5472.1765

    Article  CAS  PubMed  Google Scholar 

  19. Herrero JF, Laird JM, López-García JA: Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 2000, 61: 169–203. 10.1016/S0301-0082(99)00051-9

    Article  CAS  PubMed  Google Scholar 

  20. Casals-Díaz L, Vivó M, Navarro X: Nociceptive responses and spinal plastic changes of afferent C-fibers in three neuropathic pain models induced by sciatic nerve injury in the rat. Exp Neurol 2009, 217: 84–95. 10.1016/j.expneurol.2009.01.014

    Article  PubMed  Google Scholar 

  21. Yoshimura M, Yonehara N: Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain. Neurosci Res 2006, 56: 21–28. 10.1016/j.neures.2006.04.015

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Q, Price DD, Callam CS, Woodruff MA, Verne GN: Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome. J Pain 2011, 12: 297–303. 10.1016/j.jpain.2010.09.002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Paszcuk AF, Gadotti VM, Tibola D, Quintão NL, Rodrigues AL, Calixto JB, Santos AR: Anti-hypernociceptive properties of agmatine in persistent inflammatory and neuropathic models of pain in mice. Brain Res 2007, 23: 124–133.

    Article  Google Scholar 

  24. Khosravani H, Zhang Y, Zamponi GW: Cellular prion protein null mice display normal AMPA receptor mediated long term depression. Prion 2008, 2: 48–50. 10.4161/pri.2.2.6628

    Article  PubMed Central  PubMed  Google Scholar 

  25. Davidson EM, Coggeshall RE, Carlton SM: Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test. Neuroreport 1997, 8: 941–946. 10.1097/00001756-199703030-00025

    Article  CAS  PubMed  Google Scholar 

  26. Beirith A, Santos ARS, Calixto JB: Mechanisms underlying the nociception and paw oedema caused by injection of glutamate into the mouse paw. Brain Res 2002, 924: 219–228. 10.1016/S0006-8993(01)03240-1

    Article  CAS  PubMed  Google Scholar 

  27. Beirith A, Santos ARS, Calixto JB: The role of neuropeptides and capsaicin sensitive fibres in glutamate-induced nociception and paw oedema in mice. Brain Res 2003, 969: 110–116. 10.1016/S0006-8993(03)02286-8

    Article  CAS  PubMed  Google Scholar 

  28. Ji RR, Rupp F: Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 1997, 17: 1776–1785.

    CAS  PubMed  Google Scholar 

  29. Santos ARS, Gadotti VM, Oliveira GL, Tibola D, Paszcuk AF, Neto A, Spindola HM, Souza MM, Rodrigues ALS, Calixto JB: Mechanisms involved in the antinociception caused by agmatine in mice. Neuropharmacology 2005, 48: 1021–1034. 10.1016/j.neuropharm.2005.01.012

    Article  CAS  PubMed  Google Scholar 

  30. Davis AM, Inturrisi CE: Attenuation of hyperalgesia by LY235959, a competitive N-methyl-D-aspartate receptor antagonist. Brain Res 2001, 894: 150–153. 10.1016/S0006-8993(00)03325-4

    Article  CAS  PubMed  Google Scholar 

  31. Li TT, Ren WH, Xiao X, Nan J, Cheng LZ, Zhang XH, Zhao ZQ, Zhang YQ: NMDA NR2A and NR2B receptors in the rostral anterior cingulate cortex contribute to pain-related aversion in male rats. Pain 2009, 146: 183–193. 10.1016/j.pain.2009.07.027

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Quartaroli M, Carignani C, Dal Forno G, Mugnaini M, Ugolini A, Arban R, Bettelini L, Maraia G, Belardetti F, Reggiani A, Trist DG, Ratti E, Di Fabio R, Corsi M: Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A. J Pharmacol Exp Ther 1999, 290: 158–169.

    CAS  PubMed  Google Scholar 

  33. Svendsen F, Tjølsen A, Rygh LJ, Hole K: Expression of long-term potentiation in single wide dynamic range neurons in the rat is sensitive to blockade of glutamate receptors. Neurosci Lett 1999, 259: 25–28. 10.1016/S0304-3940(98)00884-2

    Article  CAS  PubMed  Google Scholar 

  34. Suzuki R, Matthews EA, Dickenson AH: Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 2001, 91: 101–109. 10.1016/S0304-3959(00)00423-1

    Article  CAS  PubMed  Google Scholar 

  35. Kalliomäki J, Granmo M, Schouenborg J: Spinal NMDA-receptor dependent amplification of nociceptive transmission to rat primary somatosensory cortex (SI). Pain 2003, 104: 195–200. 10.1016/S0304-3959(03)00002-2

    Article  PubMed  Google Scholar 

  36. Meotti FC, Carqueja CL, Gadotti VM, Tasca CI, Walz R, Santos AR: Involvement of cellular prion protein in the nociceptive response in mice. Brain Res 2007, 1151: 84–90.

    Article  CAS  PubMed  Google Scholar 

  37. Martins VR, Beraldo FH, Hajj GN, Lopes MH, Lee KS, Prado MM, Linden R: Prion protein: orchestrating neurotrophic activities. Curr Issues Mol Biol 2010, 12: 63–86.

    CAS  PubMed  Google Scholar 

  38. Zamponi GW, Stys PK: Role of prions in neuroprotection and neurodegeneration: a mechanism involving glutamate receptors? Prion 2009, 3: 187–189. 10.4161/pri.3.4.9549

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Lapergue B, Demeret S, Denys V, Laplanche JL, Galanaud D, Verny M, Sazdovitch V, Baulac M, Haïk S, Hauw JJ, Bolgert F, Brandel JP, Navarro V: Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus. Neurology 2010, 74: 1995–1999. 10.1212/WNL.0b013e3181e39703

    Article  CAS  PubMed  Google Scholar 

  40. Ratté S, Vreugdenhil M, Boult JK, Patel A, Asante EA, Collinge J, Jefferys JG: Threshold for epileptiform activity is elevated in prion knockout mice. Neuroscience 2011, 179: 56–61.

    Article  PubMed  Google Scholar 

  41. Prusiner SB: Prion diseases and the BSE crisis. Science 1997, 278: 245–251. 10.1126/science.278.5336.245

    Article  CAS  PubMed  Google Scholar 

  42. Prusiner SB: Prions. Proc Natl Acad Sci USA 1998, 95: 13363–13383. 10.1073/pnas.95.23.13363

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Colby DW, Prusiner SB: Prions. Cold Spring Harb Perspect Biol 2011, in press.

    Google Scholar 

  44. Muller WE, Ushijima H, Schroder HC, Forrest JM, Schatton WF, Rytik PG, Heffner-Lauc M: Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures. Eur J Pharmacol 1993, 246: 261–267. 10.1016/0922-4106(93)90040-G

    Article  CAS  PubMed  Google Scholar 

  45. Spencer MD, Knight RS, Will RG: First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features. BMJ 2002, 324: 1479–1482. 10.1136/bmj.324.7352.1479

    Article  PubMed Central  PubMed  Google Scholar 

  46. Macleod MA, Stewart GE, Zeidler M, Will R, Knight R: Sensory features of variant Creutzfeldt-Jakob disease. J Neurol 2002, 249: 706–711. 10.1007/s00415-002-0696-2

    Article  PubMed  Google Scholar 

  47. Reichman O, Tselis A, Kupsky WJ, Sobel JD: Onset of vulvodynia in a woman ultimately diagnosed with Creutzfeldt-Jakob disease. Obstet Gynecol 2010, 115: 423–425. 10.1097/AOG.0b013e3181b80294

    Article  PubMed  Google Scholar 

  48. Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C: Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992, 356: 577–582. 10.1038/356577a0

    Article  CAS  PubMed  Google Scholar 

  49. Dubuisson D, Dennis SG: The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977, 4: 161–74.

    Article  CAS  PubMed  Google Scholar 

  50. Hunskaar S, Hole K: The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 1987, 30: 103–114. 10.1016/0304-3959(87)90088-1

    Article  CAS  PubMed  Google Scholar 

  51. Tjølsen A, Hole K: Animal Models of Analgesia. In The Pharmacology of Pain. Volume 130. Springer-Verlag, Berlin; 2001:1–20.

    Chapter  Google Scholar 

  52. Hylden JL, Wilcox GL: Intrathecal morphine in mice: a new technique. Eur J Pharmacol 1980, 67: 313–316. 10.1016/0014-2999(80)90515-4

    Article  CAS  PubMed  Google Scholar 

  53. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33: 87–107. 10.1016/0304-3959(88)90209-6

    Article  CAS  PubMed  Google Scholar 

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This work was supported by an operating grant to GWZ from the PrioNet Canada. GWZ is a Scientist of the Alberta Heritage Foundation for Medical Research (AHFMR) and a Canada Research Chair in Molecular Neurobiology. VMG is supported by an AHFMR Fellowship and by a Fellowship from the Hotchkiss Brain Institute (HBI). We thank Dr. Clint Doering for genotyping and breeding paradigms, Dr. Frank R. Jirik for providing the outbred PrP null mouse line, and Stephan Bonfield for the blind analysis for experiment 1.

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Correspondence to Gerald W Zamponi.

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VMG designed and performed experiments, data analysis and wrote the article. GWZ supervised the research project and edited the manuscript. The authors read and approved the final manuscript

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Gadotti, V.M., Zamponi, G.W. Cellular prion protein protects from inflammatory and neuropathic pain. Mol Pain 7, 59 (2011).

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