Biomedical subjects

Jen-Kun Cheng

Publications and source records attributed to Jen-Kun Cheng.

11 recordsLinked to original sources

PubMed2025

CtBP1-LSD1 complex drives ErbB2 activation via H3K9me2 demethylation in DRGs during paclitaxel-induced neuropathic pain.

Paclitaxel (PTX), a commonly utilized chemotherapy drug, is linked to peripheral neuropathy, which limits dosing and significantly affects patients' quality of life. C-terminal binding protein 1 (CtBP1) is a transcriptional coregulator that participates in epigenetic gene regulation, but its role in PTX-induced neuropathic pain remains unclear. In this study, the role of CtBP1 in PTX-induced neuropathic pain is examined, with a focus on its epigenetic regulation in the dorsal root ganglia (DRGs). PTX administration markedly increased CtBP1 protein levels in DRG neurons, which coincided with the development and continuation of mechanical allodynia and thermal hyperalgesia in rat models. Our findings also revealed that CtBP1 interacts with the histone demethylase LSD1-a regulator of H3K9me2-at ErbB2 promoter sites in DRG neurons. PTX treatment increased CtBP1 protein levels, which subsequently induced LSD1 expression and decreased H3K9me2 protein levels at the ErbB2 promoter, indicating epigenetic activation of ErbB2 signaling in DRG neurons implicated in neuropathic pain. Reducing either CtBP1 or LSD1 expression reversed ErbB2 upregulation and attenuated PTX-induced pain sensitivity. These results suggest that the CtBP1-LSD1 complex epigenetically increases ErbB2 expression in DRG neurons, contributing to PTX-induced neuropathy. Targeting the CtBP1-LSD1 pathway could represent a promising therapeutic strategy for the treatment of chemotherapy-induced neuropathic pain.

Animals↗

PubMed2007

Effects of intrathecal injection of T-type calcium channel blockers in the rat formalin test.

T-type Ca2+ channels have been implicated in the induction of long-term potentiation, a synaptic plasticity involved in the central sensitization that contributes to the generation of inflammatory pain, in spinal sensory neurons. In this study, we examined the effects of intrathecal T-type Ca2+ channel blockers, mibefradil, ethosuximide and NiCl2, in the rat formalin test, an inflammatory pain model. Biphasic characteristic nociceptive behaviors were induced by intraplantar injection of formalin (5% formaldehyde, 50 microl) in Sprague-Dawley rats and monitored at 0-9 min (phase 1) and 10-60 min (phase 2) after formalin injection. Intrathecal pretreatment with mibefradil (50-500 microg) and NiCl2 (1-10 microg) dose-dependently decreased the flinch numbers and biting and licking time in both phases. The ID50s of mibefradil in inhibiting the phases 1 and 2 flinch responses were 74.3+/-4.6 and 100.9+/-8.7 microg, respectively, and those of NiCl2 were 2.7+/-1.1 and 3.3+/-0.1 microg, respectively. Ethosuximide, at the doses up to 1200 microg, however, did not affect the nociceptive responses in both phases. It is suggested that spinal T-type Ca2+ channels may play a role in formalin-induced inflammatory pain. The ineffectiveness of ethosuximide is discussed.

Animals↗

PubMed2006

Mechanisms of the antinociceptive action of gabapentin.

Gabapentin, a gamma-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA(B) receptors consisting of GABA(B1a) and GABA(B2) subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-alpha-amino acid transporter, activating ATP-sensitive K(+) channels, activating hyperpolarization-activated cation channels, and modulating Ca(2+) current by selectively binding to the specific binding site of [(3)H]gabapentin, the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the alpha(2)delta subunit of spinal N-type Ca(2+) channels is very likely the analgesic action target of gabapentin.

Amines↗

PubMed2006

The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?

Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.

Adenosine Triphosphate↗

PubMed2005

Delayed tension pneumothorax during surgery.

Tension pneumothorax is a life-threatening emergency that rapidly results in cardiopulmonary arrest. It requires prompt diagnosis and treatment. We present 2 cases from our practice, 1 caused by blunt chest trauma and the other resulting from laparoscopic surgery. Both were successfully treated by insertion of a chest tube. The diagnosis and treatment of intraoperative pneumothorax is discussed together with a review of the literature.

Adult↗

PubMed2005

Expression of A-type K channel alpha subunits Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory interneurons and colocalization with pain-modulating molecules.

Voltage-gated K(+) channel alpha subunits Kv 4.2 and Kv 4.3 are the major contributors of somatodendritic A-type K(+) currents in many CNS neurons. A recent hypothesis suggests that Kv 4 subunits may be involved in pain modulation in dorsal horn neurons. However, whether Kv 4 subunits are expressed in dorsal horn neurons remains unknown. Using immunohistochemistry, we found that Kv 4.2 and Kv 4.3 immunoreactivity was concentrated in the superficial dorsal horn, mainly in lamina II. Both Kv 4.2 and Kv 4.3 appeared on many rostrocaudally orientated dendrites, whereas Kv 4.3 could be also detected from certain neuronal somata. Kv 4.3(+) neurons were a subset of excitatory inerneurons with calretinin(+)/calbindin(-)/PKCgamma(-) markers, and a fraction of them expressed micro-opioid receptors. Kv 4.3(+) neurons also expressed ERK 2 and mGluR 5, which are molecules related to the induction of central sensitization, a mechanism mediating nociceptive plasticity. Together with the expression of Kv 4.3 in VR 1(+) DRG neurons, our data suggest that Kv C4 subunits could be involved in pain modulation.

Animals↗

PubMed2004

Predicting blood pressure change caused by rapid injection of propofol during anesthesia induction with a logistic regression model.

BACKGROUND: Propofol is a common intravenous agent for induction and maintenance of anesthesia. The advantage of propofol is rapid recovery of consciousness when the continuous infusion is stopped. Additionally, it has antiemetic effect of reducing postoperative nausea and vomiting. On the other hand, rapid infusion of propofol is painful and may cause hypotension. In this study, we aimed to develop a logistic regression model to accurately predict blood pressure change caused by rapid infusion of propofol. METHODS: Seventeen variables (including demographic data, past medical history, laboratory data, and blood pressure before induction) were assessed in 200 patients who received propofol for induction of anesthesia for routine surgery. A logistic regression model was derived using these values as independent variables to predict whether a patient would suffer a significant blood pressure change (> 30% decrease from baseline). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the performance of our prediction model. RESULTS: A cut-off value of 0.17 in the logistic regression model predicted decreased blood pressure with 90.0% sensitivity and, 67.3% specificity. The area under the receiver operating characteristic curve was 0.855. CONCLUSIONS: Our prediction model predicts propofol-induced hypotension with acceptable accuracy. Because of the straightforward mathematic formula used, our model can be integrated effortlessly into a hospital information system, providing a reliable and useful decision support for clinical anesthesia staff.

Adolescent↗

PubMed2003

Antiallodynic effects of intrathecal orexins in a rat model of postoperative pain.

Orexin A and B (hypocretin 1 and 2) are the endogenous ligands of orexin receptors, a G-protein-coupled orphan receptor family containing orexin 1 (OX1) and orexin 2 (OX2) types. Orexin A induces analgesia in acute and inflammatory pain models. We further elucidated the possible antiallodynic effect of intrathecal orexins in a rat model of postoperative pain. Mechanical allodynia was induced by incising the rat hind paw and evaluated with the withdrawal threshold to von Frey filament stimulation. Intrathecal orexin A (0.03-1 nmol) and orexin B (0.1-3 nmol) dose dependently attenuated the incision-induced allodynia. Orexin A (ED50 = 0.06 nmol) is more potent than orexin B. The effects of orexin A and B were abolished by their respective antibodies, but not by naloxone, and were attenuated by suramin and strychnine, the P2X purinergic and glycine receptor antagonists, respectively. SB-334867, an OX1 receptor antagonist, at 30 nmol completely blocked the effect of orexin A but, even at 100 nmol, only partially antagonized the effect of orexin B. Orexin A antibody, SB-334867, suramin, strychnine, or naloxone enhanced the incision-induced allodynic response. It is concluded that intrathecal orexins reduce incision-induced allodynia through OX1 receptors. Glycine and P2X purinergic receptors, but not opioid receptors, might be involved in the antiallodynic effects of orexins. Endogenous orexin might be released after incision injury to activate the spinal OX1 receptors as an endogenous analgesic protector.

Animals↗

PubMed2003

Magnesium chloride and ruthenium red attenuate the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain.

BACKGROUND: Gabapentin, a gamma-aminobutyric acid analog anticonvulsant, has been shown to possess antinociceptive effects in animal models and clinical trials. An endogenous binding site of [3H]gabapentin has been revealed to be the alpha(2)delta subunit of voltage-dependent Ca2+ channels. Magnesium chloride, ruthenium red, and spermine have been shown to modulate [3H]gabapentin binding to this binding site in vitro. In this study, the authors examined whether intrathecal magnesium chloride, ruthenium red, or spermine could affect the antiallodynic effect of intrathecal gabapentin in a rat model of postoperative pain. METHODS: Under isoflurane anesthesia, male Sprague-Dawley rats received an incision over the plantar surface of the right hind paw to produce punctate mechanical allodynia. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before incision, 2 h after incision, and every 30 min after intrathecal coadministration of gabapentin with normal saline or different doses of magnesium chloride, ruthenium red, or spermine for 2 h. RESULTS: Intrathecal gabapentin (30, 100, 200 microg) dose-dependently reduced incision-induced allodynia. Hexahydrated magnesium chloride (5, 10, 20 microg) and ruthenium red (0.2, 2, 20 ng) noncompetitively inhibited the antiallodynic effect of gabapentin. Spermine at doses not inducing motor weakness (30, 60 microg) did not affect the antiallodynic effect of gabapentin. The antiallodynic effect of intrathecal morphine (1.5 microg) was not affected by hexahydrated magnesium chloride (20 microg), ruthenium red (20 ng), or spermine (60 microg). CONCLUSIONS: These results provide behavioral evidence to support that the alpha(2)delta subunit of Ca2+ channels may be involved in the antiallodynic action of intrathecal gabapentin in the postoperative pain model.

Acetates↗

PubMed2002

Tracheal intubation condition--a comparison between one minute after rocuronium alone, one minute after rocuronium combined with atracurium and one minute after atracurium with rocuronium at one minute priming interval.

BACKGROUND: Rocuronium, a monoquaternary steroid analogue of vecuronium, is designed to provide a rapid onset of action. Experimentally, it has been shown that two non-depolarizing neuromuscular relaxants administered together can produce either a neuromuscular block of a size expected to be the sum of the individual doses (additive effect) or a larger neuromuscular block (synergistic effect). Experimental observations have suggested that during onset rocuronium acts synergistically with other nondepolarizing agents, but that at a steady state the combined action is additive. METHODS: To investigate whether rocuronium can speed up the onset of atracurium for intubation, 120 patients who consented to receive elective surgery requiring tracheal intubation were randomly assigned to 3 equally divided groups to receive one of the following three different combinations of muscle relaxants: twice ED95 of rocuronium (0.6 mg/kg group 1), an equipotent mixture of ED95 of rocuronium and atracurium (0.3 mg/kg and 0.25 mg/kg respectively, group 2), and rocuronium 0.1 mg/kg to prime atracurium 0.42 mg/kg at 1 min interval. Intubation conditions were assessed 1 minute after intravenous muscle relaxant injection, and scored as good, acceptable and poor based on four clinical evaluators: the ease of laryngoscopy (score of 1-3), the relaxation of vocal cord (1-3), the degree of coughing (1-3), and movement of extremity (1-3). Adding up together, intubation condition that scored 4-5 was considered to be good, 6-7 acceptable, and 8-12 poor. RESULTS: The conditions produced in the rocuronium and the mixture groups were similar and both were moderately better than those of the priming group. Good intubation conditions were achieved in 58% patients of the rocuronium group, 63% of the mixture group and 43% of the priming group. By Pearson Chi-square test, the comparisons did not show statistical significance between groups. CONCLUSIONS: Statistically, rocuronium alone, mixture of equipotent atracurium and rocuronium, and using rocuronium to prime atracurium all provided similar onset for satisfactory intubation.

Adult↗

PubMedDate not supplied

Does gabapentin act as an agonist at native GABA(B) receptors?

Gabapentin, a novel anticonvulsant and analgesic, is a gamma-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABA(A) or GABA(B) receptors. It was recently reported to be a selective agonist at GABA(B) receptors containing GABA(B1a)-GABA(B2) heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native GABA(B) receptors using a rat model of postoperative pain in vivo and periaqueductal gray (PAG) slices in vitro; PAG contains GABA(B) receptors, and their activation results in antinociception. An intrathecal injection of gabapentin or baclofen, a GABA(B) receptor agonist, induced antiallodynia in this postoperative pain model. Intrathecal injection of GABA(B) receptor antagonists CGP 35348 and CGP 55845 antagonized baclofen- but not gabapentin-induced antiallodynia. In ventrolateral PAG neurons, baclofen activated G-protein-coupled inwardly rectifying K(+) (GIRK) channels in a manner blocked by CGP 35348 or CGP 55845. However, gabapentin displayed no effect on the membrane current. In neurons unaffected by gabapentin, baclofen activated GIRK channels through GABA(B) receptors. It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro.

Amines↗