Enhanced excitability and suppression of A-type K+ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis

2006 ◽  
Vol 291 (3) ◽  
pp. G424-G431 ◽  
Author(s):  
Guang-Yin Xu ◽  
John H. Winston ◽  
Mohan Shenoy ◽  
Huaizhi Yin ◽  
Pankaj Jay Pasricha
Keyword(s):  
Chronic Pancreatitis ◽  
Visceral Pain ◽  
Treated Group ◽  
Fluorescence Labeling ◽  
Intractable Pain ◽  
Type I ◽  
Drg Neurons ◽  
Adult Rats ◽  
Inactivation Curve ◽  
Steady State Inactivation

Chronic pancreatitis (CP) is a relatively common disorder, characterized by glandular insufficiency and chronic, often intractable, pain. The mechanism of pain in CP is poorly understood. We have previously developed a model of trinitrobenzene sulphonic acid (TNBS)-induced CP that results in nociceptive sensitization in rats. This study was designed to examine changes in the excitability and alteration of voltage-gated K+ currents of dorsal root ganglia (DRG) neurons innervating the pancreas. CP was induced in adult rats by an intraductal injection of TNBS. DRG neurons innervating the pancreas were identified by 1,1′-dioleyl-3,3,3′,3-tetramethylindocarbocyanine methanesulfonate fluorescence labeling. Perforated patch-clamp recordings were made from acutely dissociated DRG neurons from control and TNBS-treated rats. Pancreas-specific DRG neurons displayed more depolarized resting potentials in TNBS-treated rats than those in controls ( P < 0.02). Some neurons from the TNBS-treated group exhibited spontaneous firings. TNBS-induced CP also resulted in a dramatic reduction in rheobase ( P < 0.05) and a significant increase in the number of action potentials evoked at twice rheobase ( P < 0.05). Under voltage-clamp conditions, neurons from both groups exhibited transient A-type ( IA) and sustained outward rectifier K+ currents ( IK). Compared with controls, the average IA but not the average IK density was significantly reduced in the TNBS-treated group ( P < 0.05). The steady-state inactivation curve for IA was displaced by ∼20 mV to more hyperpolarized levels after the TNBS treatment. These data suggest that TNBS treatment increases the excitability of pancreas-specific DRG neurons by suppressing IA density, thus identifying for the first time a specific molecular mechanism underlying chronic visceral pain and sensitization in CP.

Cyclic AMP selectively reduces the N-type calcium current component of mouse sensory neurons in culture by enhancing inactivation

1989 ◽  
Vol 61 (1) ◽  
pp. 97-105 ◽  
Author(s):  
R. A. Gross ◽  
R. L. Macdonald
Keyword(s):  
Steady State ◽  
Cyclic Amp ◽  
Cholera Toxin ◽  
Calcium Current ◽  
Calcium Currents ◽  
Resting Membrane Potential ◽  
High Threshold ◽  
Drg Neurons ◽  
Inactivation Curve ◽  
Steady State Inactivation

1. The single-electrode voltage-clamp technique was used to assess the effect of elevated intracellular cyclic AMP levels on the three calcium current components of mouse dorsal root ganglion (DRG) neurons in culture. 2. Neither forskolin, cholera toxin, nor 8-Br-cyclic AMP affected the isolated transient low-threshold (T) calcium current. 3. When calcium currents were evoked at clamp potentials (Vc) positive to -20 mV from holding potentials (Vh) near the resting membrane potential, the calcium current consisted primarily of the transient high-threshold (N) and the slowly inactivating high-threshold (L) calcium current components. Under these conditions forskolin, cholera toxin, and 8-Br-cyclic AMP reduced the peak calcium current but had little or no effect on the late (greater than or equal to 300 ms) calcium current. When calcium currents were evoked from very negative Vh, however, there was no effect of these compounds. 4. Forskolin had no effect on the voltage-dependence of the current-voltage relation, nor on the rate of recovery of the calcium current from inactivation. 5. In other experiments, current traces were fitted using a multiexponential curve-fitting program that determined the amplitudes and inactivation time constants (tau i) of the three calcium current components. Forskolin selectively reduced the magnitude of the (curve-fitted) N current, and reduced its tau i. 6. Forskolin also enhanced steady-state inactivation of the N current, producing a -7.5 mV shift in the steady-state inactivation curve. 7. Cholera toxin, forskolin, and 8-Br-cyclic AMP had similar effects on calcium currents in mouse DRG neurons in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Clinical characteristics and quality of life among Sri Lankan patients with chronic pancreatitis

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052097987
Author(s):  
Umesh Jayarajah ◽  
Thisaru Widyarathne ◽  
Metthananda Nawarathne ◽  
Sivananthan Raguvaran ◽  
Nishanthan Subramaniam ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Weight Loss ◽  
Chronic Pancreatitis ◽  
Clinical Characteristics ◽  
Considerable Proportion ◽  
Intractable Pain ◽  
Life Questionnaire ◽  
European Organization ◽  
Loss Of Appetite

Objective We aimed to describe the clinical characteristics of chronic pancreatitis (CP) and patient quality of life (QOL) in a resource-limited setting. Methods We performed a cross-sectional study including patients with clinical and radiological features of CP. We collected clinical data and assessed QOL using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire. Results We included 103 patients (median age 44 years, 84 men). Median age at symptom onset was 36 (4–78) years. Around 70% of patients had diabetes mellitus and 62.1% had consumed alcohol; 36 (35%) were current smokers. The mean overall global QOL score was 68.7. Most patients (91.3%) sought treatment from multiple centers. Nineteen (18.5%) had pancreatic stone disease, 38 (36.9%) had persistent abdominal pain (median severity 7.8/10, 59 (57.3%) had steatorrhea, and 56 (54.4%) had jaundice. Poor QOL was significantly associated with weight loss, loss of appetite, and intractable pain. No correlation with age, sex, or alcohol consumption was noted. Conclusion A considerable proportion of patients with CP had troublesome symptoms. Intractable pain, loss of appetite, and weight loss were significantly associated with poor QOL. Further assessment is needed of patients’ psychosocial well-being and its association with QOL.

Interaction of NHE1 and TRPA1 activity in DRG neurons isolated from adult rats and its role in inflammatory nociception

Neuroscience ◽  
2021 ◽  
Author(s):  
Vladimir A. Martínez-Rojas ◽  
Ana B. Salinas-Abarca ◽  
Norma L. Gómez-Víquez ◽  
Vinicio Granados-Soto ◽  
Francisco Mercado ◽  
...  
Keyword(s):  
Drg Neurons ◽  
Adult Rats ◽  
Inflammatory Nociception

Developmental study of benzodiazepine effects on monosynaptic GABAA-mediated IPSPs of rat hippocampal neurons

1993 ◽  
Vol 70 (3) ◽  
pp. 1076-1085 ◽  
Author(s):  
C. Rovira ◽  
Y. Ben-Ari
Keyword(s):  
Hippocampal Neurons ◽  
Receptor Agonist ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Developmental Study ◽  
Type I ◽  
Gamma Aminobutyric Acid ◽  
Adult Rats ◽  
Young Rats ◽  
In Cells

1. The effects of type I (BZ1) and type II (BZ2) benzodiazepine receptor ligands on monosynaptic gamma-aminobutyric acid (GABA)A-mediated inhibitory postsynaptic potentials (IPSPs) and on responses to exogenously applied GABA were studied using intracellular recordings from CA3 pyramidal cells of rat hippocampal slices taken at different postnatal stages [postnatal day 4 (P4)-P35)]. 2. The effects of midazolam, a BZ1 and BZ2 receptor agonist, were tested on the monosynaptic IPSPs at different stages. Monosynaptic, bicuculline-sensitive IPSPs were evoked by hilar stimulation in presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) antagonists [6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and D(-)2-amino-5-phosphonopentanoic acid (50 microM)]. Midazolam at 300 nM maximally increased the duration and amplitude of monosynaptic GABAA-mediated IPSPs in neurons from pups (P4-P6, n = 6) and young (P7-P12, n = 8) and adult (P25-P35, n = 9) rats. All the effects of midazolam on IPSPs were reversed by the antagonist Ro 15-1788 (10 microM). 3. The effect of midazolam was also tested on the response to exogenously applied GABA (5 mM) in the presence of tetrodotoxine [TTX (1 microM)]. In neurons from young rats (n = 9), midazolam (1 nM-1 microM) did not change the responses to exogenously applied GABA, whereas in adult rats (n = 8) midazolam maximally increased GABA currents at 30 nM. 4. The effect of zolpidem, a BZ1 receptor agonist, was tested on monosynaptic IPSPs and GABA currents at different stages. Zolpidem (10 nM-1 microM) was inactive in cells from young rats (n = 12). In neurons from adult rats, zolpidem maximally increased the duration and amplitude of the monosynaptic IPSPs at 300 nM (n = 5) and the amplitude of GABA current at 30-100 nM (n = 5). 5. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (300 nM), an inverse agonist of BZ1 and BZ2 receptors, decreased the amplitude and duration of monosynaptic IPSPs in neurons from pups (n = 3) and young (n = 4) and adult (n = 5) rats. In all cases, full recovery was obtained after exposure to R0 15-1788 (10 microM). DMCM (300 nM-10 microM) failed to reduce GABA responses in cells from young (n = 3) or adult (n = 7) rats. 6. Results indicate that the regulation by benzodiazepine of GABAA-mediated IPSPs varies with the developmental stage.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Peak force and maximal shortening velocity of soleus fibers after non-weight-bearing and resistance exercise

1997 ◽  
Vol 82 (1) ◽  
pp. 189-195 ◽  
Author(s):  
Jeffrey J. Widrick ◽  
Robert H. Fitts
Keyword(s):  
Resistance Exercise ◽  
Elevated Level ◽  
Fiber Diameter ◽  
Weight Bearing ◽  
Normal Weight ◽  
Peak Force ◽  
Type I ◽  
Shortening Velocity ◽  
Adult Rats ◽  
Cross Sectional

Widrick, Jeffrey J., and Robert H. Fitts. Peak force and maximal shortening velocity of soleus fibers after non-weight-bearing and resistance exercise. J. Appl. Physiol. 82(1): 189–195, 1997.—This study examined the effectiveness of resistance exercise as a countermeasure to non-weight-bearing-induced alterations in the absolute peak force, normalized peak force (force/fiber cross-sectional area), peak stiffness, and maximal shortening velocity ( V o) of single permeabilized type I soleus muscle fibers. Adult rats were subjected to one of the following treatments: normal weight bearing (WB), non-weight bearing (NWB), or NWB with exercise treatments (NWB+Ex). The hindlimbs of the NWB and NWB+Ex rats were suspended for 14 days via tail harnesses. Four times each day, the NWB+Ex rats were removed from suspension and performed 10 climbs (∼15 cm each) up a steep grid with a 500-g mass (∼1.5 times body mass) attached to their tail harness. NWB was associated with significant reductions in type I fiber diameter, absolute force, normalized force, and stiffness. Exercise treatments during NWB attenuated the decline in fiber diameter and absolute force by almost 60% while maintaining normalized force and stiffness at WB levels. Type I fiber V oincreased by 33% with NWB and remained at this elevated level despite the exercise treatments. We conclude that in comparison to intermittent weight bearing only (J. J. Widrick, J. J. Bangart, M. Karhanek, and R. H. Fitts. J. Appl. Physiol. 80: 981–987, 1996), resistance exercise was more effective in attenuating alterations in type I soleus fiber absolute force, normalized force, and stiffness but was less effective in restoring type I fiber V oto WB levels.

Spinal Cord Stimulation for Visceral Pain Related to Chronic Pancreatitis: Report of 2 Cases

2014 ◽  
Vol 81 (3-4) ◽  
pp. 651.e17-651.e19 ◽  
Author(s):  
Francesco Vergani ◽  
Alexandros Boukas ◽  
Nitin Mukerji ◽  
Nishma Nanavati ◽  
Claire Nicholson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Chronic Pancreatitis ◽  
Spinal Cord Stimulation ◽  
Visceral Pain

Synaptic and Somatic Effects of Axotomy in the Intact, Innervated Rat Sympathetic Neuron

2006 ◽  
Vol 95 (5) ◽  
pp. 2832-2844 ◽  
Author(s):  
Oscar Sacchi ◽  
Maria Lisa Rossi ◽  
Rita Canella ◽  
Riccardo Fesce
Keyword(s):  
Sympathetic Neuron ◽  
Equilibrium Potential ◽  
Voltage Sensitivity ◽  
Inactivation Curve ◽  
Epsc Amplitude ◽  
Control Value ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Cervical Ganglia

A biophysical description of the axotomized rat sympathetic neuron is reported, obtained by the two-electrode voltage-clamp technique in mature, intact superior cervical ganglia in vitro. Multiple aspects of neuron functioning were tested. Synaptic conductance activated by the whole presynaptic input decreased to 29% of the control value (0.92 μS per neuron) 1 day after axotomy and to 18% after 3 days. Despite the decrease in amplitude of the macroscopic current, miniature excitatory postsynaptic current (mEPSC) mean conductance, acetylcholine (ACh) equilibrium potential, and EPSC decay time constant were unaffected. Synaptic efficacy was tested during paired-pulse or maintained stimulation (5, 10, and 15 Hz, 10-s duration). Quantal release in axotomized neurons was preserved during the tetanus despite the reduction of the initial EPSC amplitude, suggesting that ACh secretion depended on the number of surviving synapses; each of them exhibited dynamic behavior during trains similar to that of normal synapses. Facilitation of EPSC amplitude was noted in 2-day axotomized neurons during the first few impulses in the train. Voltage-dependent potassium currents (the delayed IKD and the transient IA) exhibited an early drastic decrease in peak amplitude; these effects persisted 7 days after axotomy. Marked changes in IA kinetics occurred after injury: the steady-state inactivation curve shifted by up to +17 mV toward positive potentials and the voltage sensitivity of inactivation removal became steeper. IA impairment was reflected in a reduced inward threshold charge for discharge and reduced spike repolarization rate. Synaptic and somatic data were applied in a mathematical model to describe the progressive decrease in the safety factor, and the eventual failure of ganglionic transmission after axotomy.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Contribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons

2001 ◽  
Vol 86 (2) ◽  
pp. 629-640 ◽  
Author(s):  
Muthukrishnan Renganathan ◽  
Theodore R. Cummins ◽  
Stephen G. Waxman
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Action Potentials ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Drg Neurons ◽  
Significant Difference ◽  
Steady State Inactivation ◽  
Current Threshold

C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels are expressed in these neurons, and the molecular identity of the TTX-R sodium channels that contribute to action potential production in these neurons has not been established. In this study, we used current-clamp recordings to compare action potential electrogenesis in Nav1.8 (+/+) and (−/−) small DRG neurons maintained for 2–8 h in vitro to examine the role of sodium channel Nav1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav1.8 (+/+) and (−/−) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav1.8 (−/−) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav1.8 (−/−) neurons [31.5 ± 2.2 (SE) mV] compared with Nav1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav1.8 (+/+) neurons, significantly faster than in Nav1.8 (−/−) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav1.8 (+/+) and (−/−) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80–90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav1.8 (−/−) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav1.8 (−/−) neurons is more sensitive to membrane depolarization than in Nav1.8 (+/+) neurons, and, in the absence of Nav1.8, is attenuated with even modest depolarization. These observations indicate that Nav1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

scholarly journals P2X3 Receptor in Primary Afferent Neurons Mediates the Relief of Visceral Hypersensitivity by Electroacupuncture in an Irritable Bowel Syndrome Rat Model

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Fang Zhang ◽  
Zhe Ma ◽  
Zhijun Weng ◽  
Min Zhao ◽  
Handan Zheng ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Rat Model ◽  
Visceral Pain ◽  
Visceral Hypersensitivity ◽  
Receptor Protein ◽  
Resting Membrane Potential ◽  
Drg Neurons ◽  
Expression Levels ◽  
Behavioral Studies ◽  
Irritable Bowel

Background. Electroacupuncture (EA) has been confirmed effectiveness in the treatment of irritable bowel syndrome (IBS), and P2X3 receptors in the peripheral and central neurons participate in the acupuncture-mediated relief of the visceral pain in IBS. Objective. To reveal the neurobiological mechanism that P2X3 receptor of colonic primary sensory neurons in the dorsal root ganglia of the lumbosacral segment is involved in the alleviation of visceral hypersensitivity by EA in an IBS rat model. Methods. The IBS chronic visceral pain rat model was established according to the method of Al-Chaer et al. EA at the bilateral He-Mu points, including ST25 and ST37, was conducted for intervention. The behavioral studies, histopathology of colon, electrophysiology, immunofluorescence histochemistry, and real-time polymerase chain reaction assays were used to observe the role of P2X3 receptor in the colon and related DRG in relieving visceral hypersensitivity by EA. Results. EA significantly reduced the behavior scores of the IBS rats under different levels (20, 40, 60, 80 mmHg) of colorectal distention stimulation and downregulated the expression levels of P2X3 receptor protein and mRNA in colon and related DRG of the IBS rats. EA also regulated the electrical properties of the membranes, including the resting membrane potential, rheobase, and action potential of colon-associated DRG neurons in the IBS rats. Conclusion. EA can regulate the P2X3 receptor protein and mRNA expression levels in the colon and related DRG of IBS rats with visceral pain and then regulate the excitatory properties of DRG neurons.

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