Preserved acute pain and impaired neuropathic pain in mice lacking protein interacting with C Kinase 1
© Wang et al; licensee BioMed Central Ltd. 2011
Received: 27 October 2010
Accepted: 3 February 2011
Published: 3 February 2011
Protein interacting with C Kinase 1 (PICK1), a PDZ domain-containing scaffolding protein, interacts with multiple different proteins in the mammalian nervous system and is believed to play important roles in diverse physiological and pathological conditions. In this study, we report that PICK1 is expressed in neurons of the dorsal root ganglion (DRG) and spinal cord dorsal horn, two major pain-related regions. PICK1 was present in approximately 29.7% of DRG neurons, most of which were small-less than 750 μm2 in cross-sectional area. Some of these PICK1-positive cells co-labeled with isolectin B4 or calcitonin-gene-related peptide. In the dorsal horn, PICK1 immunoreactivity was concentrated in the superficial dorsal horn, where it was prominent in the postsynaptic density, axons, and dendrites. Targeted disruption of PICK1 gene did not affect basal paw withdrawal responses to acute noxious thermal and mechanical stimuli or locomotor reflex activity, but it completely blocked the induction of peripheral nerve injury-induced mechanical and thermal pain hypersensitivities. PICK1 appears to be required for peripheral nerve injury-induced neuropathic pain development and to be a potential biochemical target for treating this disorder.
Neurotransmission requires spatial and functional assembly of signal transduction machinery at the plasma membrane. The postsynaptic density, an electron-dense cytoskeletal structure beneath the plasma membrane of excitatory synapses, is one site where receptors, channels, and effectors organize to mediate signaling . The postsynaptic density contains membrane proteins such as AMPA receptor (AMPAR) subunits and NMDA receptor subunits, signal transduction molecules such as protein kinase C alpha (PKCα) and neuronal nitric oxide synthase, and scaffolding proteins [1, 2]. Most scaffolding proteins contain one or more PDZ (PSD-95/Dlg/ZO-1) amino acid domains [1, 3, 4]. Through PDZ domain interaction, they assemble intracellular signaling complexes around synaptic receptors, regulate synaptic and non-synaptic receptor trafficking and functions, and participate in many physiological and pathological processes triggered via the activation of synaptic receptors [1, 3–6].
Protein interacting with C Kinase 1 (PICK1), a PDZ domain-containing scaffolding protein that is enriched in the postsynaptic density, initially was reported to interact with PKCα  and subsequently was found to bind to synaptic AMPAR subunit GluR2 in central neurons [8–10]. We recently reported that, via its PDZ domain, PICK1 interacts with GluR2 and PKCα, recruits intracellular PKCα to synaptic GluR2, and leads to GluR2 phosphorylation at Ser880 [11–14]. This phosphorylation disrupts the interaction between synaptic GluR2 and the anchor protein AMPAR-binding protein/glutamate receptor-interacting protein; promotes synaptic GluR2 internalization; and increases synaptic GluR2-lacking, Ca2+ permeable AMPARs in dorsal horn neurons [11–14]. In addition, we have shown previously that preventing dorsal horn GluR2 internalization through targeted disruption of PICK1 gene attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity during the maintenance period . These findings suggest that spinal PICK1 may participate in the maintenance of persistent inflammatory pain by promoting dorsal horn GluR2 internalization. However, the expression and distribution of PICK1 in the pain-related regions of the nervous system have not been carefully studied. In addition, CFA-induced inflammatory pain and nerve injury-induced neuropathic pain might share some intracellular signaling pathways in their central mechanisms , but whether PICK1 is also involved in the development and maintenance of nerve injury-induced persistent neuropathic pain is unknown.
In the present study, we first characterized the expression and distribution of PICK1 in two major pain-related regions, the dorsal root ganglion (DRG) and spinal cord dorsal horn. Then, we addressed the role of PICK1 in neuropathic pain induced by fifth lumbar (L5) spinal nerve ligation (SNL) and distal transection. Finally, we examined whether peripheral nerve injury, like peripheral inflammation, induces dorsal horn GluR2 internalization and whether this induction requires spinal PICK1 under neuropathic pain conditions.
Materials and methods
Male mice (10-12 weeks old) and male Sprague-Dawley rats (225-250 g) were housed on a standard 12-h light/dark cycle, with water and food pellets available ad libitum. PICK1 knockout (KO) mice (C57BL/6J genetic background) were generated as described previously . Male PICK1 KO mice and wild-type (WT) littermates were obtained by interbreeding PICK1 heterozygous mice. To minimize intra- and inter-individual variability of behavioral outcome measures, animals were trained for 1-2 days before behavioral testing was performed. Animal experiments were conducted with the approval of the Animal Care and Use Committee at Johns Hopkins University and were consistent with the ethical guidelines of the National Institutes of Health and the International Association for the Study of Pain. All efforts were made to minimize animal suffering and to reduce the number of animals used. The experimenters were blind to mouse genotype during the behavioral testing.
Intrathecal administration of PICK1 antisense (AS) oligodeoxynucleotide (ODN)
To further confirm the results from PICK1 KO mice, we used a PICK1 AS ODN approach to knock down PICK1 in spinal cord and DRG of rats. Rats were used because the subarachnoid space of mice is too small to implant the intrathecal (i.th.) polyethylene (PE-10) catheter that is required for repeated ODN injections. The design of PICK1 AS ODN, its control missense (MS) ODN, and their i.th. administration have been described in our previous study . Briefly, an i.th. PE-10 catheter was inserted into the subarachnoid space at the rostral level of the spinal cord lumbar enlargement segments through an incision at the atlanto-occipital membrane [14, 17, 18]. One week later, rats that showed no neurological deficits received an i.th. injection of saline (10 μl; control), AS ODN (10 μg/10 μl), or MS ODN (10 μg/10 μl) once daily for 4 days. On the second day after ODN injection, an L5 SNL model of neuropathic pain or sham surgery was performed as described below.
Neuropathic pain model
An L5 SNL model of neuropathic pain was produced in mice and rats according to the method described previously [6, 18, 19]. In brief, animals were anesthetized with isoflurane, and a dorsolateral skin incision was made on the lower back. The sixth lumbar transverse process was identified and freed of its muscle attachment and then removed. The underlying fifth lumbar nerve root was isolated, ligated with a silk suture (6-0 in mice; 3-0 in rats), and transected just distal to the ligature. After appropriate hemostasis, the skin and muscle layers were closed with a silk suture. In the sham group, the surgical procedure was identical to that described above, except that the spinal nerve was not ligated or transected. Paw withdrawal responses to thermal and mechanical stimuli on the ipsilateral and contralateral sides were examined 1 day before and then at various time point after SNL or sham surgery as described below.
Tail-flick assay: The mouse (5 WT and 5 KO mice) was placed in a Plexiglas cylinder. A tail-flick apparatus (Model 33B Tail Flick Analgesia Meter, IITC Life Science, Woodland Hills, CA, USA) with a radiant heat source connected to an automatic timer was used to assess the analgesic response. A cut-off time latency of 10 sec was used to avoid tissue damage to the tail. Tail-flick latencies were measured as the time required to induce a tail flick after applying radiant heat to the skin of the tail. Each trial was repeated five times at 5-min intervals.
Paw withdrawal responses to noxious thermal stimuli: The mouse (10 WT and 10 KO mice) or rat (15 rats) was placed in a Plexiglas chamber on a glass plate above a light box. Radiant heat from Model 336 Analgesia Meter (IITC Life Science) was applied by aiming a beam of light through a hole in the light box through the glass plate to the middle of the plantar surface of each hind paw. When the animal lifted its foot, the light beam automatically shut off. The length of time between the start of the light beam and the foot lift was defined as the paw withdrawal latency. Each trial was repeated five times at 5-min intervals for each side. A cut-off time of 20 sec was used to avoid tissue damage to the hind paw.
Paw withdrawal responses to repeated mechanical stimuli: The mouse (10 WT and 10 KO mice) or rat (15 rats) was placed in a Plexiglas chamber on an elevated mesh screen. In mice, two calibrated von Frey monofilaments (0.24 and 4.33 mN; Stoelting Co., Wood Dale, IL, USA) were employed. Each von Frey filament was applied to the hind paw for approximately 1 sec, and each trial was repeated 10 times to both hind paws. In rats, a single trial of mechanical stimuli consisted of eight applications of a calibrated von Frey filament (8.01 mN) within a 2-3-sec period. Each trial was repeated 10 times at 3-min intervals on each hind paw. The occurrence of paw withdrawal in each of these 10 trials was expressed as a percent response frequency [(number of paw withdrawals/10 trials) × 100 = % response frequency], and this percentage was used as an indication of the amount of paw withdrawal.
Locomotor function testing
The following tests were performed with the experimenter blind to the mouse genotype (5 WT and 5 KO mice): (1) Placing reflex: the experimenter held the animal's hind limbs slightly lower than the forelimbs and brought the dorsal surfaces of the hind paws into contact with the edge of a table. The experimenter recorded whether the hind paws were placed on the table surface reflexively. (2) Grasping reflex: the experimenter placed the animal on a wire grid and recorded whether the hind paws grasped the wire on contact. (3) Righting reflex: the experimenter placed the animal's back on a flat surface and noted whether it immediately assumed the normal upright position. Scores for placing, grasping, and righting reflexes were based on counts of each normal reflex exhibited in five trials. In addition, the animal's general behaviors, including spontaneous activity, were observed.
The mice (6 WT and 1 KO mouse) were deeply anesthetized with isoflurane and perfused with 4% paraformaldehyde in phosphate buffer (0.1 M, pH 7.4). The L4-5 spinal cord segments and DRGs were harvested, post-fixed in the same fixative solution for 2-4 h, and cryoprotected by immersion in 30% sucrose overnight at 4°C. The transverse sections (20 μm) were cut on a cryostat, and four sets of sections from WT mice were collected. PICK1 immunohistochemical staining alone was performed on the first set of sections. Briefly, the sections were blocked for 1 h at 37°C in 0.01 M phosphate-buffered saline (PBS) containing 10% normal goat serum plus 0.3% Triton X-100. The sections were incubated in primary rabbit antibody for PICK1 (1:500)  for 48 h at 4°C. The specificity and selectivity of this antibody were reported previously . The sections were finally incubated in biotinylated goat anti-rabbit IgG (1:200; Vector Laboratories, Burlingame, CA) for 1 h at 37°C followed by avidin-biotin-peroxidase complex (1:100; Vector) for 1 h at 37°C. The immune reaction product was visualized by catalysis of 3,3-diaminobenzidine by horseradish peroxidase in the presence of 0.01% H2O2.
Double-immunofluorescence histochemistry for PICK1/calcitonin gene-related peptide (CGRP) and for PICK1/NeuN was performed on the second and third sets of sections, respectively. Briefly, the sections were incubated sequentially with a mixture of rabbit polyclonal anti-PICK1 (1:500) and mouse monoclonal antibody to CGRP (1:200; Sigma, St. Louis, MO) or mouse monoclonal anti-NeuN (1:600; Chemicon, Temecula, CA) overnight at 4°C and a mixture of goat anti-rabbit IgG conjugated with Cy3 and donkey anti-mouse IgG conjugated with Cy2 (1:200; Jackson ImmunoResearch, West Grove, PA) for 1 h at room temperature. Double-fluorescence histochemistry for PICK1/biotinylated isolectin (IB)4 was performed on the fourth set of sections. Briefly, the sections were incubated sequentially with a mixture of IB4 (1:100; Sigma) and rabbit polyclonal anti-PICK1 (1:500) overnight at 4°C and a mixture of goat anti-rabbit IgG conjugated with Cy3 and Cy2-labeled avidin (1:200, Sigma) for 1 h at room temperature. In control double-labeling experiments, either of the primary antibodies was omitted or replaced with normal IgG or serum. All immunofluorescence-labeled sections were rinsed in 0.01 M PBS and mounted onto gelatin-coated glass slides. Cover slips were applied with a mixture of 50% glycerin and 2.5% triethylene diamine in 0.01 M PBS. The sections from double-labeling experiments were further observed with a confocal laser-scanning microscope by using laser excitation lines of 443-488 nm with appropriate emission filter for Cy3 (550-570 nm) or for Cy2 (492-510 nm).
For size distribution analysis of PICK1-positive cells within the L5 DRG, two sections were randomly selected from the first set of sections of each animal. All labeled and unlabeled cells with nuclei were counted. Cell profiles were outlined and cell area was calculated with the imaging software Image-Pro Plus (Media Cybernetics, Silver Spring, MD). For the analysis of PICK1/CGRP and PICK1/IB4 double-labeling within the L5 DRG, two sections each were randomly selected from the second, third, and fourth set of sections of each animal. Images were captured directly off the confocal laser-scanning microscope at 20 × objective magnification. Single-labeled (PICK1, CGRP, NeuN, or IB4) and double-labeled (PICK1/CGRP, PICK1/NeuN, or PICK1/IB4) neurons were counted, respectively.
Post-embedding immunogold labeling and electron microscopy
Post-embedding immunogold labeling was carried out as described previously [6, 12]. Briefly, WT mice (n = 2) were perfused transcardially with 4% paraformaldehyde + 0.5% glutaraldehyde. Cryoprotected sections from the L5 superficial dorsal horns were frozen in Leica CPC and freeze-substituted into Lowicryl HM-20 in a Leica AFS freeze substitution instrument. Ultrathin sections were labeled with polyclonal rabbit antibody for PICK1. Controls for specificity and selectivity of these antibodies were performed as described previously [16, 20]. Areas for study were selected at random from the superficial dorsal horn at low magnification (i.e., synapses not visible) and then micrographs of synapses were taken at high magnification.
Subcellular fractionation of proteins
Biochemical fractionation was carried out according to previous studies with minor modification [6, 12, 19]. The mice (10 WT and 10 KO mice/time point) were sacrificed by decapitation, and the tissues from L4 and L5 segments were dissected. The ipsilateral spinal cord was separated from the contralateral spinal cord under a surgical microscope and collected. Ipsilateral L4 or L5 spinal cords from two mice were pooled together and homogenized in homogenization buffer (50 mM Tris-HCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM phenymethylsulfonyl fluoride, 1 μM leupeptin, 2 μM pepstain A). After the homogenate was centrifuged at 1,000 × g for 20 min at 4°C, the supernatant (S1, total soluble fraction) was collected and the pellet (P1, nuclei and debris fraction) discarded. The supernatant was centrifuged at 10,000 × g for 20 min to produce a pellet (P2) and supernatant (S2). The P2 was lysed hypo-osmotically in water and centrifuged at 25,000 × g to produce a final pellet (P3). The S2 was considered to be the crude cytosolic fraction and the P3 the crude synaptosomal membrane fraction.
Western blotting analysis
After protein concentration was measured, proteins (30 μg) were heated for 5 min at 98°C and loaded onto 4% stacking/7.5% separating SDS-polyacrylamide gels for protein separation. The protein was then electrophoretically transferred onto a nitrocellulose membrane. The membrane was blocked with 3% nonfat dry milk and subsequently incubated for 1 h with polyclonal rabbit primary antibody for PICK1 (1:1,000), GluR2 (1:500; Upstate/CHEMICON, Temecula, CA), PKCα (1:1,000; Santa Cruz Biotechnology, Santa Cruz, CA), acid-sensing ion channel (ASIC) 1 (1:1000; Santa Cruz), ASIC2 (1:1000; Santa Cruz), or N-cadherin (1:1,000; BD Biosciences, Palo Alto, CA), and monoclonal mouse primary antibody for β-actin (1:3,000; Santa Cruz Biotechnology). The proteins were detected by horseradish peroxidase-conjugated anti-rabbit or anti-mouse secondary antibodies and visualized with chemiluminescence reagents provided with the ECL kit (Amersham Pharmacia Biotech, Piscataway, NJ) and exposure to film. The intensity of blots was quantified with densitometry. The blot density from naïve animals was set as 100%.
The results from the behavioral tests, Western blotting, and immunohistochemistry were analyzed statistically with a one-way or two-way analysis of variance (ANOVA). Data are presented as means ± SEM. When ANOVA showed significant difference, pairwise comparisons between means were tested by the post hoc Tukey method. Significance was set at P < 0.05. The statistical software package SigmaStat (Systat, San Jose, CA) was used to perform all statistical analyses.
Mean (SEM) changes in locomotor test
Neuropathic pain is a chronic condition that affects millions of people worldwide. Current treatments are often inadequate, ineffective, or produce potentially severe adverse effects. Therefore, the search for novel therapeutic and preventive strategies is essential. Here, we report that PICK1, a PDZ domain-containing scaffolding protein, might be required for the induction of nerve injury-induced neuropathic pain, suggesting that PICK1 may be a new target for the prevention and/or treatment of this disorder.
The present study demonstrated that PICK1 was expressed in two major pain-related regions, DRG and dorsal horn. We found that approximately 30% of DRG neurons were positive for PICK1 and that most of such neurons were small. Both peptidergic and non-peptidergic neurons were represented. In the dorsal horn, PICK1-positive terminals, fibers, and cell bodies were concentrated on the superficial dorsal horn, especially in lamina I and inner lamina II. Under electron microscopy, immunogold labeling for PICK1 was associated with the postsynaptic density in the dendrites of the superficial dorsal horn neurons. In line with this finding, we previously showed that PICK1 was expressed more highly in the dorsal horn than in the ventral horn or DRG . Abundant expression of PICK1 in small DRG neurons and superficial dorsal horn neurons suggests that it might participate in transmission and modulation of nociceptive information.
PICK1 plays distinct roles in acute pain and neuropathic pain. The present study showed intact response to noxious mechanical and thermal stimuli in naïve PICK1 KO mice, indicating that PICK1 might not be involved in acute pain transmission. In contrast, PICK1 knockout abolished nerve injury-induced pain hypersensitivity during the development and maintenance periods. Moreover, PICK1 knockdown in spinal cord and DRG significantly attenuated nerve injury-induced development of pain hypersensitivity. These findings suggest that PICK1 in spinal cord and DRG contributes to neuropathic pain. Our previous study demonstrated that spinal PICK1 deficiency also attenuated pain hypersensitivity during the maintenance period of CFA-induced inflammatory pain . Moreover, we found that this effect might be attributable to reduction of NMDA receptor/PKC-triggered dorsal horn GluR2 internalization in CFA-induced inflammatory pain maintenance [12–14]. We expected to observe this mechanism in neuropathic pain as well. However, we detected no significant change in the level of GluR2 in cytosolic or synaptosomal membrane fractions from dorsal horn of WT or PICK1 KO mice after L5 SNL. These results indicate that SNL-induced nerve injury input, unlike CFA-induced inflammatory input, does not promote dorsal horn GluR2 internalization. Hence, PICK1 may participate in neuropathic pain development via other potential mechanisms, even as it binds to its partners PKCα and GluR2.
In addition to interacting with GluR2, PICK1 interacts specifically with the C-termini of ASIC1 and ASIC2 in central neurons via its PDZ domain [23, 24]. ASIC1 is expressed predominantly in small-diameter DRG neurons, whereas ASIC2 is localized to the plasma membrane of small-, medium-, and large-diameter cells of the DRG [25–27]. Disrupting the mouse ASIC2 gene markedly reduces the sensitivity of a specific component of mechanosensation . Moreover, PICK1 potentiates PKA phosphorylation of ASIC1 and increases ASIC2 current by enhancing its phosphorylation by PKC . It seems that the anti-hyperalgesic effect caused by PICK1 deficiency in neuropathic pain might be due to a reduction in function of DRG ASIC1 and ASIC2.
PICK1's PDZ domain also binds to metabotropic glutamate receptor subunit 7 (mGluR7) in central neurons. An inhibitory presynaptic receptor, mGluR7 is expressed in the DRG neurons and primary afferent terminals [30, 31]. It is activated under neuropathic pain conditions, but not under normal conditions [32–34]. Because PICK1 inhibits PKC phosphorylation of mGluR7 [9, 35, 36], it is possible that PICK1 deficiency causes a loss of inhibition of mGluR7 phosphorylation and potentiates mGluR7 activation. Activated mGluR7 would then inhibit glutamate release from primary afferents and result in an antinociceptive effect in neuropathic pain. The possibility that DRG PICK1 might contribute to neuropathic pain by regulating ASIC1, ASIC2, and mGluR7 functions remains to be further confirmed. It is noteworthy that during neuropathic pain PICK1 still interacts with other proteins, such as Eph receptor tyrosine kinase , dopamine transporter , and class I ADP-ribosylation factors . Whether these interactions are involved in neuropathic pain is unknown.
In summary, we showed that PICK1 was expressed in the DRG and superficial dorsal horn neurons. Behavioral studies demonstrated that knockout of PICK1 abolished pain hypersensitivity during nerve injury-induced neuropathic pain development and maintenance, without affecting acute pain or locomotor function. Although the mechanism of this antinociceptive effect in neuropathic pain is still unclear, PICK1 appears to be a potential target for prevention and/or treatment of this disorder.
This work was supported by National Institutes of Health (NS058886), the Blaustein Pain Research Fund, Mr. David Koch and the Patrick C. Walsh Prostate Cancer Research Fund, and Brain Science Institute at the Johns Hopkins University (Y.X.T.), Department of Anesthesiology (M.Y.), and the Intramural Research Program of NIDCD (R.S.P.). We thank Mrs. Ya-Xian Wang for help with the immunogold experiments. The authors thank Claire Levine, MS, for editorial assistance.
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