scholarly journals Responses of cutaneous C-fiber afferents and spinal microglia after hindlimb cast immobilization in rats

2021 ◽  
Vol 71 (1) ◽  
Author(s):  
Hiroki Ota ◽  
Haruna Takebe ◽  
Kazue Mizumura ◽  
Toru Taguchi
Keyword(s):  
Mechanical Response ◽  
Response Threshold ◽  
Lumbar Spinal Cord ◽  
Cast Immobilization ◽  
C Fibers ◽  
Electrophysiological Recordings ◽  
C Fiber ◽  
Lumbar Spinal ◽  
Limb Immobilization

AbstractPrevious studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization.

Differential blockade of cat dorsal root C fibers by various chloride solutions

1972 ◽  
Vol 36 (5) ◽  
pp. 569-583 ◽  
Author(s):  
J. Stovall King ◽  
Don L. Jewett ◽  
Howard R. Sundberg
Keyword(s):  
Hypertonic Saline ◽  
Choline Chloride ◽  
Isotonic Saline ◽  
Chloride Ion ◽  
Content Type ◽  
Persistent Effect ◽  
C Fibers ◽  
C Fiber ◽  
Intrathecal Infusion

✓ A possible mechanism by which intrathecal infusion of partially frozen saline might relieve patients of chronic pain has been studied by applying hypertonic saline to the dorsal rootlets of cats in vitro. The supernatant of partially thawed normal saline was found to be hypertonic. Persistent block of C fibers, detected by a collision method, occurred after the rootlets had been exposed to saline from 500 to 2500 mOsm/L for 15 min followed by 15 min of isotonic saline. Few of the A fibers were blocked by this procedure, but both A and C fibers were blocked when solutions of 3500 mOsm/L were used. Differential blockage of C fibers could also be produced with hypotonic saline and with distilled water. Localized cooling, to 2°C for 25 min, had no persistent effect on C fiber conduction, and when cooling was combined with hypertonic saline there was no potentiation of the differential blockade caused by the saline. Hypertonic solutions of sucrose or sodium nitrate produced no persistent differential block; most A and C fibers recovered. However, choline chloride was as effective as sodium chloride in giving a differential blockade. It seems that chloride ion plays a major role in establishing the persistent C fiber blockade observed when dorsal rootlets are exposed to hypertonic saline.

B2 Receptor–Mediated Enhanced Bradykinin Sensitivity of Rat Cutaneous C-Fiber Nociceptors During Persistent Inflammation

2001 ◽  
Vol 86 (6) ◽  
pp. 2727-2735 ◽  
Author(s):  
Ratan Kumar Banik ◽  
Yasuko Kozaki ◽  
Jun Sato ◽  
Lajos Gera ◽  
Kazue Mizumura
Keyword(s):  
Receptor Subtype ◽  
Response Curves ◽  
C Fibers ◽  
B1 Receptor ◽  
Persistent Inflammation ◽  
C Fiber ◽  
Inflammatory State ◽  
Tissue Sensitivity ◽  
Sensitizing Effect

Bradykinin (BK), which has potent algesic and sensitizing effect on nociceptors, is of current interest in understanding the mechanisms of chronic pain. BK response is mediated by B2 receptor in normal conditions; however, findings that B1 receptor blockade alleviated hyperalgesia in inflammation have been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 receptor agonists or antagonists during inflammation. In addition, previous studies reported the change in BK sensitivity of nociceptors during short-lasting inflammation, and data in persistent inflammation are lacking. Therefore we investigated whether an experimentally induced persistent inflammatory state modulates the BK sensitivity of nociceptors and which receptor subtype plays a more important role in this condition. Complete Freund's adjuvant was injected into the rat-tail and after 2–3 wk, persistent inflammation developed, which was prominent in the ankle joint. Using an in vitro skin-saphenous nerve preparation, single-fiber recordings were made from mechano-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, and their responses were compared with those obtained from C-fibers tested similarly in normal animals. BK at 10−8 M excited none of the 10 C-fibers in normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animals, and at 10−6 M BK excited all of the 11 inflamed C-fibers (or 94% of 36 tested C-fibers) but only 4 of 10 (or 45% of 58 tested C-fibers) in normal animals. Thus the concentration-response curves based on the incidence of BK induced excitation, and the total number of impulses evoked in response to BK were significantly shifted to the left. Moreover, an increased percentage of the inflamed C-fibers responded to 10−6 M BK with bursting or high-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to consecutive second and third 10−6 M BK stimulation. A B2 receptor antagonist (d-Arg-[Hyp3, Thi5,8,d-phe7]-BK) completely eliminated BK responses in inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg9-[Leu8]-BK) had no effect. Selective B1 receptor agonist (Des-Arg10-Kallidin) excited 46% ( n = 13) of inflamed C-fibers at 10−5 M concentration, which is 1,000 times higher than that of BK needed to excite the same percentage of inflamed C-fibers. We conclude that in chronically inflamed tissue, sensitivity of C-fiber nociceptors to BK, which is B2 receptor mediated, is strongly increased and that B1 receptor may not be important to a persistent inflammatory state, at least at the primary afferent level.

scholarly journals Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Ewelina Rojewska ◽  
Agnieszka M. Jurga ◽  
Wioletta Makuch ◽  
Ferenz Zador ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cell Activation ◽  
Microglial Cell ◽  
Lumbar Spinal Cord ◽  
Orphanin Fq ◽  
Binding Assays ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Lumbar Spinal

Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Ourin vitrostudy showed that minocycline reducedNOPmRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

scholarly journals Mechanisms of the adenosine A2Areceptor-induced sensitization of esophageal C fibers

2016 ◽  
Vol 310 (3) ◽  
pp. G215-G223 ◽  
Author(s):  
M. Brozmanova ◽  
L. Mazurova ◽  
F. Ru ◽  
M. Tatar ◽  
Y. Hu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Mechanical Response ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Receptor Potential ◽  
P2x Receptor ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor ◽  
Stimulation Of

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2Areceptor. Here we addressed the hypothesis that stimulation of the adenosine A2Areceptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2Areceptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10–60 mmHg) in a concentration-dependent fashion (1–100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2Aantagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031 . Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2Areceptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

Serotonin increases excitability of rabbit C-fiber neurons by two distinct mechanisms

1989 ◽  
Vol 67 (2) ◽  
pp. 584-591 ◽  
Author(s):  
E. P. Christian ◽  
G. E. Taylor ◽  
D. Weinreich
Keyword(s):  
Impulse Activity ◽  
Repetitive Firing ◽  
Receptor Subtype ◽  
Potential Contribution ◽  
Action Potential Firing ◽  
C Fibers ◽  
C Fiber ◽  
Ganglion Neurons

Serotonin (5-HT) increases impulse activity in visceral afferent C-fibers in vivo. A 5-HT-induced membrane depolarization may partially account for this effect. Here, we examined the potential contribution of an additional mechanism to the 5-HT-mediated increase in impulse activity. Approximately 40% of rabbit visceral C-fiber neurons exhibit a protracted (greater than 3 s) spike afterhyperpolarization (AHPslow) that is a major determinant of repetitive firing properties in these neurons. Intracellular recording methods were applied to rabbit nodose ganglion neurons in vitro to assess whether 5-HT could increase excitability through effects on the AHPslow. Results revealed a concentration-dependent 5-HT-mediated depression of the AHPslow amplitude and duration that was accompanied by decreased accommodation of action potential firing. Experiments with 5-HT receptor antagonists further showed that this autacoid depressed the AHPslow through a different 5-HT receptor subtype than that subserving the 5-HT-induced depolarization. Thus the AHPslow represents a distinct locus where 5-HT can increase the impulse activity of these visceral C-fiber afferents.

Characterization of Aδ- and C-Fibers Innervating the Plantar Rat Hindpaw One Day After an Incision

2002 ◽  
Vol 87 (2) ◽  
pp. 721-731 ◽  
Author(s):  
Esther M. Pogatzki ◽  
G. F. Gebhart ◽  
Timothy J. Brennan
Keyword(s):  
Spontaneous Activity ◽  
Mechanical Response ◽  
Tissue Injury ◽  
Mechanical Stimulus ◽  
Response Threshold ◽  
Mechanical Stimuli ◽  
Median Response ◽  
Sham Procedure ◽  
C Fibers ◽  
Afferent Fibers

Primary hyperalgesia after tissue injury is suggested to result from sensitization of primary afferent fibers, but sensitization to mechanical stimuli has been difficult to demonstrate. In the companion study, sensitization of mechano-responsive Aδ- and C-fibers did not explain pain behaviors 45 min after an incision in the rat hindpaw. In the present study, we examined mechanical response properties of Aδ- and C-fibers innervating the glabrous skin of the plantar hindpaw in rats 1 day after an incision or sham procedure. In behavioral experiments, median withdrawal thresholds to von Frey filaments were reduced from 522 mN before to 61 mN 2 and 20 h after incision; median withdrawal thresholds after sham procedure were stable (522 mN). Responses to a nonpunctate mechanical stimulus were increased after incision. In neurophysiological experiments in these same rats, 67 single afferent fibers were characterized from the left tibial nerve 1 day after sham procedure ( n = 39) or incision ( n = 28); electrical stimulation was used as the search stimulus to identify a representative population of Aδ- and C-fibers. In the incision group, 11 fibers (39%) had spontaneous activity with frequencies ranging from 0.03 to 39.3 imp/s; none were present in the sham group. The median response threshold of Aδ-fibers was less in the incision (56 mN, n = 13) compared with sham (251 mN, n = 26) group, mainly because the proportion of mechanically insensitive afferents (MIAs) was less (8 vs. 54% after sham procedure). Median C-fiber response thresholds were similar in incised (28 mN, n = 15) and sham rats (56 mN, n = 13). Responsiveness to monofilaments was significantly enhanced in Aδ-fibers 1 day after incision; stimulus response functions of C-fibers after incision and after sham procedure did not differ significantly. Only Aδ-fibers but not C-fibers sensitized to the nonpunctate mechanical stimulus. The size of receptive fields was increased in Aδ- and C-fibers 1 day after incision. The results indicate that sensitization of Aδ- and C-fibers is apparent 1 day after incision. Because sensitization of afferent fibers to mechanical stimuli correlated with behavioral results, sensitization may contribute to the reduced withdrawal threshold after incision. Spontaneous activity in Aδ- and C-fibers may account for nonevoked pain behavior and may also contribute to mechanical hyperalgesia by amplifying responses centrally.

scholarly journals Glucose is an adequate energy substrate for the depolarizing action of GABA and glycine in the neonatal rat spinal cord in vitro

2012 ◽  
Vol 107 (11) ◽  
pp. 3107-3115 ◽  
Author(s):  
Rémi Bos ◽  
Laurent Vinay
Keyword(s):  
Spinal Cord ◽  
Energy Supply ◽  
Reversal Potential ◽  
Neonatal Rat ◽  
Lumbar Spinal Cord ◽  
Primary Afferent ◽  
Artificial Cerebrospinal Fluid ◽  
High Concentrations ◽  
Lumbar Spinal

In vitro studies have repeatedly demonstrated that the neurotransmitters γ-aminobutyric acid (GABA) and glycine depolarize immature neurons in many areas of the CNS, including the spinal cord. This widely accepted phenomenon was recently challenged by experiments showing that the depolarizing action of GABA on neonatal hippocampus and neocortex in vitro was prevented by adding energy substrates (ES), such as the ketone body metabolite dl-β-hydroxybutyric acid (DL-BHB), lactate, or pyruvate to the artificial cerebrospinal fluid (ACSF). It was suggested that GABA-induced depolarizations in vitro might be an artifact due to inadequate energy supply when glucose is the sole energy source, consistent with the energy metabolism of neonatal rat brain being largely dependent on ESs other than glucose. Here we examined the effects of these ESs (DL-BHB, lactate, pyruvate) on inhibitory postsynaptic potentials (IPSPs) recorded from neonatal rat lumbar spinal cord motoneurons (MNs), in vitro. We report that supplementing the ACSF with physiologic concentrations of DL-BHB, lactate, or pyruvate does not alter the reversal potential of IPSPs ( EIPSP). Only high concentrations of pyruvate hyperpolarized EIPSP. In addition, the depolarizing action of GABA on primary afferent terminals was not affected by supplementing the ACSF with ES at physiologic concentrations. We conclude that depolarizing IPSPs in immature MNs and the primary afferent depolarizations are not caused by inadequate energy supply. Glucose at its standard concentration appears to be an adequate ES for the neonatal spinal cord in vitro.

Neonatal Death in Mice Lacking Cardiotrophin-like Cytokine is Associated with Multifocal Neuronal Hypoplasia

2008 ◽  
Vol 46 (3) ◽  
pp. 514-519 ◽  
Author(s):  
X. Zou ◽  
B. Bolon ◽  
J. K. Pretorius ◽  
C. Kurahara ◽  
J. McCabe ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Ventral Horn ◽  
Lumbar Spinal Cord ◽  
Facial Nucleus ◽  
In Ovo ◽  
Neuron Survival ◽  
Motor Neuron Survival ◽  
Lumbar Spinal

Mice with null mutations of ciliary neurotrophic factor (Cntf) receptor alpha (Cntf-Rα), or cytokine-like factor 1 (Clf), one component of Cntf-II (a heterodimeric Cntf-Rα ligand), die as neonates from motor neuron loss affecting the facial nucleus and ventral horn of the lumbar spinal cord. Exposure to cardiotrophin-like cytokine (Clc), the other putative Cntf-II element, supports motor neuron survival in vitro and in ovo. Confirmation that Clc ablation induces an equivalent phenotype to Clf deletion would support a role for Clc in the functional Cntf-II complex. In this study, Clc knockout mice had decreased facial motility, did not suckle, died within 24 hours, and had 32% and 29% fewer motor neurons in the facial nucleus and lumbar ventral horn, respectively; thus, Clc is essential for motor neuron survival during development. The concordance of the Clc knockout phenotype with those of mice lacking Cntf-Rα or Clf bolsters the hypothesis that Clc participates in Cntf-II.

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