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ABSTRACT: The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. PERSPECTIVE: The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.
The journal of pain: official journal of the American Pain Society 09/2012; 13(10):945-58. · 3.78 Impact Factor
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ABSTRACT: The previous study indicated that aquaporin 4 (AQP4) deficiency attenuated opioid physical dependence. However, the underlying mechanism remains unknown. In the present study, the effects of AQP4 deficiency on the expression of three factors, protein kinase C (PKC) α, PKCγ and c-Fos in the spinal cord, which are known to be concerned with spinal neuronal sensitization and opiate dependence, were investigated in AQP4 knockout mice using Western blotting analysis. It was observed that AQP4 deficiency reduced the score of naloxone-precipitated abstinent jumping after repeated morphine administration compared with wild-type (P < 0.001). Meanwhile, the protein levels of PKCα and c-Fos in the spinal cord of AQP4 knockout mice were significantly higher than those in the wild-type mice; while the expression of PKCγ was decreased remarkably by AQP4 knockout during the withdrawal (P < 0.01). These data suggest that AQP4 deficiency-attenuated morphine withdrawal responses may be partially attributed to the changes in the spinal expression of PKCα, PKCγ or c-Fos.
Sheng li xue bao: [Acta physiologica Sinica] 08/2012; 64(4):365-71.
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ABSTRACT: The pivotal role of estrogens in the pain sensitivity has been investigated in many ways. Traditionally, it is ascribed to the slow genomic changes mediated by classical nuclear estrogen receptors (ER), ERα and ERβ, depending on peripheral estrogens. Recently, it has become clear that estrogens can also signal through membrane ERs (mERs), such as G-protein-coupled ER1 (GPER1), mediating the non-genomic effects. However, the spinal specific role played by ERs and the underlying cellular mechanisms remain elusive. The present study investigated the rapid estrogenic regulation of nociception at the spinal level. Spinal administration of 17β-estradiol (E2), the most potent natural estrogen, acutely produced a remarkable mechanical allodynia and thermal hyperalgesia without significant differences among male, female and ovariectomized (Ovx) rats. E2-induced the pro-nociceptive effects were partially abrogated by ICI 182,780 (ERs antagonist), and mimicked by E2-BSA (a mER agonist). Inhibition of local E2 synthesis by 1,4,6-Androstatrien-3,17-dione (ATD, a potent irreversible aromatase inhibitor), or blockade of ERs by ICI 182,780 produced an inhibitory effect on the late phase of formalin nociceptive responses. Notably, lumbar puncture injection of G15 (a selective GPER1 antagonist) resulted in similar but more efficient inhibition of formalin nociceptive responses as compared with ICI 182,780. At the cellular level, the amplitude and decay time of spontaneous inhibitory postsynaptic currents were attenuated by short E2 or E2-BSA treatment in spinal slices. These results indicate that estrogen acutely facilitates nociceptive transmission in the spinal cord via activation of membrane-bound estrogen receptors.
Neurochemical Research 08/2012; · 2.24 Impact Factor
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ABSTRACT: Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17β-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer's tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ERα, ERβ, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ERα and ERβ antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ERβ (but not ERα) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ERβ in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2.
Journal of Biological Chemistry 08/2012; 287(40):33268-81. · 4.77 Impact Factor
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ABSTRACT: The rostral anterior cingulate cortex (rACC) is a key structure of pain affect. Whether and how estrogen in the rACC regulates pain-related negative emotion remains unclear. Behaviorally, using formalin-induced conditioned place aversion (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that estrogen receptor (ER) inhibitor ICI 182, 780 (ICI, 7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol) or inhibitor of aromatase androstatrienedione into the rACC completely blocked F-CPA in either sex. An analogous effect was also observed in ovariectomy rats. Furthermore, exogenous estrogen in the absence of a formalin noxious stimulus was sufficient to elicit CPA (E-CPA) in both sexes by activating the membrane estrogen receptors (mERs) and N-methyl-D-aspartic acid (NMDA) receptors (NMDARs). Electrophysiologically, we demonstrated that estrogen acutely enhanced the glutamatergic excitatory postsynaptic currents (EPSCs) in rACC slices by increasing the ratio of NMDA-EPSCs to α-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid -EPSCs and presynaptic glutamate release. Interestingly, a brief exposure to estrogen elicited a persistent enhancement of NMDA-EPSCs, and this NMDA-long-term potentiation required the activation of the mERs, protein kinase A and NMDAR subunit NR2B. Finally, estrogen induced rapid dendritic spine formation in cultured rACC neurons. These results suggest that estrogen in the rACC, as a neuromodulator, drives affective pain via facilitating NMDA receptor-mediated synaptic transmission.
Cerebral Cortex 07/2012; · 6.54 Impact Factor
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ABSTRACT: Tetanic stimulation of the sciatic nerve induces long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal dorsal horn and persistent pain, suggesting that spinal LTP may be a substrate for central sensitization of the pain pathway. However, its cellular mechanism remains unclear. The present study provides electrophysiological and behavioral evidence for the involvement of ryanodine receptor (RyR) in the induction of spinal LTP and persistent pain in rats. The specific inhibitor of ryanodine receptor, ryanodine and dantrolene, dose dependently blocked the induction, but not maintenance, of spinal LTP and reduced persistent pain behaviors induced by tetanic sciatic stimulation. Both cyclic ADP ribose (cADPR), an endogenous agonist of RyR, and (±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester (Bay K 8644), an agonist of L-type calcium channel, attenuated ryanodine-induced inhibition. Immunohistochemistry and electron microscopic observation showed that RyR subtypes RyR1 and RyR3 were located in the spinal dorsal horn. The results suggest that RyRs are involved in synaptic plasticity of the spinal pain pathway and may be a novel target for treating pain. © 2012 Wiley Periodicals, Inc.
Journal of Neuroscience Research 05/2012; 90(5):1096-104. · 2.74 Impact Factor
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ABSTRACT: The rostral anterior cingulate cortex (rACC) is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors (NMDARs) are highly expressed in the rACC and mediate pain-related affect by activating a signaling pathway that involves cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and/or extracellular regulated kinase (ERK)/cAMP-response element-binding protein (CREB). The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC.
Immunohistochemistry and Western blot analysis were used to separately assess the expression of phospho-ERK (pERK) and phospho-CREB (pCREB) in vitro and in vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB.
Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up-regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antagonist DL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycine-binding site, or degradation of endogenous D-serine, a co-agonist for the glycine site, significantly decreased the up-regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB.
Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect.
Neuroscience Bulletin 02/2012; 28(1):77-87. · 1.31 Impact Factor
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ABSTRACT: The present study aimed to investigate the potential roles of spinal microglia and downstream molecules in the induction of spinal long-term potentiation (LTP) and mechanical allodynia by tetanic stimulation of the sciatic nerve (TSS).
Spinal LTP was induced in adult male Sprague-Dawley rats by tetanic stimulation of the sciatic nerve (0.5 ms, 100 Hz, 40 V, 10 trains of 2-s duration at 10-s intervals). Mechanical allodynia was determined using von Frey hairs. Immunohistochemical staining and Western blot were used to detect changes in glial expression of interleukin-18 (IL-18) and IL-18 receptor (IL-18R).
TSS induced LTP of C-fiber-evoked field potentials in the spinal cord. Intrathecal administration of the microglial inhibitor minocycline (200 μg/20 μL) 1 h before TSS completely blocked the induction of spinal LTP. Furthermore, after intrathecal injection of minocycline (200 μg/20 μL) by lumbar puncture 1 h before TSS, administration of minocycline for 7 consecutive days (once per day) partly inhibited bilateral allodynia. Immunohistochemistry showed that minocycline inhibited the sequential activation of microglia and astrocytes, and IL-18 was predominantly colocalized with the microglial marker Iba-1 in the spinal superficial dorsal horn. Western blot revealed that repeated intrathecal injection of minocycline significantly inhibited the increased expression of IL-18 and IL-18Rs in microglia induced by TSS.
The IL-18 signaling pathway in microglia is involved in TSS-induced spinal LTP and mechanical allodynia.
Neuroscience Bulletin 02/2012; 28(1):49-60. · 1.31 Impact Factor
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ABSTRACT: Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K(+) channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K(+) channels in DRG neurons during bone cancer pain. The A-type K(+) currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K(+) channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K(+) currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K(+) channel blocker 4-AP or pandinotoxin-Kα, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K(+) channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K(+) channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain.
Pain 12/2011; 153(3):562-74. · 5.78 Impact Factor
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ABSTRACT: The present study is to investigate whether the extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) signaling pathway contributes to the initiation of chronic constriction injury (CCI)-induced neuropathic pain in rats. Mechanical allodynia was assessed by measuring the hindpaw withdrawal threshold in response to a calibrated series of von Frey hairs. Thermal hyperalgesia was assessed by measuring the latency of paw withdrawal in response to a radiant heat source. The expressions of phosphor-ERK (pERK) and phosphor-CREB (pCREB) were examined using Western blot analysis and immunohistochemistry. An early robust increase in the expression of pERK on the spinal cords ipsilateral to injury was observed on day 1 after CCI, when the CCI-induced behavioral hypersensitivity had not developed yet. Moreover, the upregulation of pERK expression in ipsilateral spinal cord was associated with the increase in pCREB expression in bilateral spinal cord. Intrathecal administration of mitogen-activated protein kinase kinase (MEK) inhibitor U0126 before CCI can efficiently block and delay the CCI-induced mechanical allodynia and thermal hyperalgesia. These data suggest that activation of ERK and CREB in the spinal cord contributes to the initiation of peripheral nerve injury-induced pain hypersensitivity, and an early intervention strategy should be proposed.
Sheng li xue bao: [Acta physiologica Sinica] 04/2011; 63(2):106-14.
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ABSTRACT: Previous studies indicated that disruption of glial function in the spinal cord enhanced electroacupuncture (EA) analgesia in arthritic rats, suggesting glia is involved in processing EA analgesia. To probe into the potential value for clinical practice, the present study was to investigate the effect of propentofylline, a glia inhibitor, on EA analgesia in rats. Mechanical allodynia induced by tetanic stimulation of sciatic nerve (TSS) was used as a pain model. On day 7 after TSS, EA treatment induced a significant increase in paw withdrawal threshold to mechanical stimulation. Intrathecal or intraperitoneal injection of propentofylline relieved TSS-induced mechanical allodynia. The combination of low dosage of propentofylline and EA produced more potent anti-allodynia than propentofylline or EA alone. Immunohistochemistry exhibited that TSS-induced activation of microglia and astrocytes was inhibited significantly by propentofylline. These results indicate that propentofylline and EA induce synergetic analgesia by interrupting spinal glial function.
Neurochemical Research 11/2010; 35(11):1780-6. · 2.24 Impact Factor
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ABSTRACT: Tetanic stimulation of the sciatic nerve (TSS) produces long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal cord. This potentiation is considered to be a substrate for long-lasting sensitization in the spinal pain pathway. Because microglia have previously been shown to regulate the induction of spinal LTP, we hypothesize that P2X7 receptors (P2X7R), which are predominantly expressed in microglia and participate in the communication between microglia and neurons, may play a role in this induction. This study investigated the potential roles of P2X7Rs in spinal LTP and persistent pain induced by TSS in rats. OxATP or BBG, a P2X7R antagonist, prevented the induction of spinal LTP both in vivo and in spinal cord slices in vitro and alleviated mechanical allodynia. Down-regulation of P2X7Rs with P2X7-siRNA blocked the induction of spinal LTP and inhibited mechanical allodynia. Double immunofluorescence showed colocalization of P2X7Rs with the microglial marker OX-42, but not with the astrocytic marker GFAP or the neuronal marker NeuN. Intrathecal injection of BBG suppressed the up-regulation of microglial P2X7Rs and increased expression of Fos in the spinal superficial dorsal horn. Further, pre-administration of BBG inhibited increased expression of the microglial marker Iba-1, phosphorylated p38 (p-p38), interleukin 1β (IL-1β) and GluR1 following TSS. Pre-administration of the IL-1 receptor antagonist (IL-1ra) blocked both the induction of spinal LTP and the up-regulation of GluR1. These results suggest that microglial P2X7Rs and its downstream signaling pathways play a pivotal role in the induction of spinal LTP and persistent pain induced by TSS.
Brain Behavior and Immunity 10/2010; 24(7):1176-89. · 4.72 Impact Factor
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ABSTRACT: Lysophosphatidic acid (LPA) is released from injured tissue and cancer cells and is involved in the induction of neuropathic pain. The present study explores whether LPA plays a role in the development of osteocarcinoma-induced pain.
The bone cancer model was established using the Walker 256 mammary gland carcinoma cell line, and cancer-related behavioral and physiological changes were observed using von Frey, X-ray and immunohistochemical methods. The role of LPA in the bone cancer model and related mechanisms were examined by using in vitro single fiber recording and western blot.
Rats exhibited severe hyperalgesia 2weeks after the cancer cell implantation. Several changes were observed at this time point including: ipsilateral dorsal root ganglion (DRG) neurons were labeled by injured neurons marker ATF3; LPA(1) receptor expression in DRG neurons was increased; sural C-fibers were more sensitive to LPA stimuli, and this response could be blocked by LPA receptor and substance P receptor antagonists.
These data indicate that LPA is involved in the induction of bone cancer pain through mechanisms of peripheral C-fibers sensitization. LPA and its downstream molecules possibly are promising therapeutic targets for treatment of cancer pain.
Life sciences 07/2010; 87(3-4):120-5. · 2.56 Impact Factor
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ABSTRACT: Morphine loses analgesic potency after repeated administration. The underlying mechanism is not fully understood. Glia are thought to be involved in morphine tolerance, and P2X(7) purinergic receptor (P2X(7)R) has been implicated in neuron-glia communication and chronic pain. The present study demonstrated that P2X(7)R immunoreactivity was colocalized with the microglial marker OX42, but not the astrocytic marker GFAP, in the spinal cord. The protein level of spinal P2X(7)R was upregulated after chronic exposure to morphine. Intrathecal administration of Brilliant Blue G (BBG), a selective P2X(7)R inhibitor, significantly attenuated the loss of morphine analgesic potency, P2X(7)R upregulation, and microglial activation. Furthermore, RNA interference targeting the spinal P2X(7)R exhibited a similar tolerance-attenuating effect. Once morphine analgesic tolerance is established, it was no longer affected by intrathecal BBG. Together, our results suggest that spinal P2X(7)R is involved in the induction but not maintenance of morphine tolerance.
Journal of Neuroscience 06/2010; 30(23):8042-7. · 7.11 Impact Factor
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ABSTRACT: The medial thalamus (MT) and anterior cingulate cortex (ACC) are essential components in mediating the affective emotional-aspect of pain. Whether ACC modulates the neuron activity in MT has not been elucidated and clarifying this point will further reveal the neurobiological mechanism underlying pain related emotions. In the present study, we used in vivo single unit recording and retrograde tracing technique to demonstrate that the majority of examined neurons in the central lateral nucleus (CL), an important nucleus of MT, responded to noxious stimulation. Tetanic stimulation in the ACC increased spike activities of nociceptive-responding neurons in the CL; retrograde tracing by fluorogold in the CL showed the positive neurons are distributed bilaterally in the ACC. Taken together, we demonstrated descending modulation to nociceptive responses of CL neurons by direct projections from the ACC, which may underlie the neuronal mechanism of negative pain emotions.
Brain research bulletin 04/2010; 81(6):574-8. · 2.18 Impact Factor
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ABSTRACT: Recent reports showed that aquaporin 4 (AQP4) deficiency potentiated morphine analgesia but attenuated chronic morphine-induced tolerance in hot-plate test, predominantly reflecting supraspinal pain response. The present study investigated the effects of AQP4 deficiency on morphine analgesia and tolerance using tail flick test, primarily reflecting spinal response. It was found that (1) chronic morphine treatment resulted in decreased expression of spinal AQP4 in mice detected by Western blotting analysis; (2) in tail flick test, AQP4 knockout mice displayed significant impaired morphine analgesia without influencing the progress of chronic tolerance; and (3) the expressions of mu-opioid receptor (MuOR) and glutamate transporter 1 (GLT-1) in AQP4 knockout mice spinal cord were lower than those in wild-type mice, whereas chronic morphine-induced alteration characteristics of spinal MuOR or GLT-1 expression were not affected by AQP4 deficiency. In conclusion, AQP4 deficiency attenuated morphine acute antinociception but did not affect chronic tolerance in tail flick test, implying a role for spinal AQP4 in morphine analgesia but not in chronic tolerance.
Journal of Molecular Neuroscience 04/2010; 42(2):140-4. · 2.50 Impact Factor
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ABSTRACT: It has been demonstrated that lysophosphatidic acid (LPA) released from injury tissue and transient receptor potential vanilloid 1 (TRPV1) receptor are implicated in the induction of chronic pain. In the present study we examined whether an interaction between LPA receptor LPA(1) and TRPV1 in dorsal root ganglion (DRG) neurons contributes to the development of bone cancer pain.
Bone cancer was established by injection of mammary gland carcinoma cells into the rat tibia. Following the development of bone cancer pain, the TRPV1 expression and capsaicin-evoked currents were up-regulated in rat DRG neurons at L(4-6) segments. Immunohistochemistry staining revealed a high co-localization of LPA(1) with TRPV1 in DRG neurons. In isolated DRG neurons, whole-cell patch recording showed that capsaicin-induced currents were potentiated by LPA in a dose-dependent manner. The potentiation was blocked by either LPA(1) antagonist, protein kinase C (PKC) inhibitor or PKCε inhibitor, but not by protein kinase A (PKA) inhibitor or Rho inhibitor. In the behavioral tests, both mechanical allodynia and thermal hyperalgesia in bone cancer rats were attenuated by LPA(1) antagonist.
LPA potentiates TRPV1 current via a PKCε-dependent pathway in DRG neurons of rats with bone cancer, which may be a novel peripheral mechanism underlying the induction of bone cancer pain.
Molecular Pain 01/2010; 6:85. · 3.53 Impact Factor
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ABSTRACT: Our previous study demonstrated that nitric oxide (NO) contributes to long-term potentiation (LTP) of C-fiber-evoked field potentials by tetanic stimulation of the sciatic nerve in the spinal cord in vivo. Ryanodine receptor (RyR) is a downstream target for NO. The present study further explored the role of RyR in synaptic plasticity of the spinal pain pathway.
By means of field potential recordings in the adult male rat in vivo, we showed that RyR antagonist reduced LTP of C-fiber-evoked responses in the spinal dorsal horn by tetanic stimulation of the sciatic nerve. Using spinal cord slice preparations and field potential recordings from superficial dorsal horn, high frequency stimulation of Lissauer's tract (LT) stably induced LTP of field excitatory postsynaptic potentials (fEPSPs). Perfusion of RyR antagonists blocked the induction of LT stimulation-evoked spinal LTP, while Ins(1,4,5)P3 receptor (IP(3)R) antagonist had no significant effect on LTP induction. Moreover, activation of RyRs by caffeine without high frequency stimulation induced a long-term potentiation in the presence of bicuculline methiodide and strychnine. Further, in patch-clamp recordings from superficial dorsal horn neurons, activation of RyRs resulted in a large increase in the frequency of miniature EPSCs (mEPSCs). Immunohistochemical study showed that RyRs were expressed in the dorsal root ganglion (DRG) neurons. Likewise, calcium imaging in small DRG neurons illustrated that activation of RyRs elevated [Ca(2+)]i in small DRG neurons.
These data indicate that activation of presynaptic RyRs play a crucial role in the induction of LTP in the spinal pain pathway, probably through enhancement of transmitter release.
Molecular Pain 01/2010; 6:1. · 3.53 Impact Factor
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Yu-Qiu Zhang,
Ning Guo,
Guangdun Peng,
Xidao Wang,
Mei Han,
Jeremy Raincrow,
Chi-Hua Chiu,
Lique M Coolen,
Robert J Wenthold, Zhi-Qi Zhao,
Naihe Jing,
Lei Yu
Pain 01/2010; 148(1):176. · 5.78 Impact Factor
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ABSTRACT: To explore the role of the extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) pathway in the induction of long-term potentiation (LTP) in the anterior cingulate cortex (ACC) that may be implicated in pain-related negative emotion.
LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK (pERK) and phospho-CREB (pCREB) were examined using immunohistochemistry method.
LTP could be induced stably in ACC slice by high frequency stimulation (2-train, 100 Hz, 1 s), while APv (an antagonist of NMDA receptor) could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 (50 micromol/L), a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 min and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB.
NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.
Neuroscience Bulletin 10/2009; 25(5):301-8. · 1.31 Impact Factor
