Role of C-fibers during acute and chronic stress on formalin-induced paw edema in rats.

Stimulation of peripheral nociceptors leads to releasing of some mediators such as substance P (SP) and Calcitonin gene-related peptide (CGRP) and contributes to the edema formation by vasodilatation induction. On the other hand glucocorticoids have anti-inflammatory action, and they are elevated in the plasma during stress. This communication reports C-fibers inflammatory role and the effects of chronic and acute stress and/or dexamethasone (as stress mimicry) on paw edema induced by formalin at presence/deficit C-fibers rats. Acute stress and dexamethasone and chronic dexamethasone have shown an anti-inflammatory effect in C-normal groups, but chronic stress had no effect on inflammation. C-fibers reduction (C-lesion) had anti-inflammatory effects. In deficit C-fibers rats, acute and chronic stress had not stronger anti-inflammatory effect, but acute dexamethasone reduced the anti-inflammatory effect of C-fibers reduction while in the same condition, chronic dexamethasone induced stronger anti-inflammatory effect. The results show C-fiber nerve produce and release the peripheral inflammatory mediators, "C-fibers reduction" decreased the paw inflammation. Counter adaptation in C-lesion animals may reduce the modulatory effects of dexamethasone on the remaining C-fibers. Acute dexamethasone diminished the "C-fibers reduction" anti-inflammatory effect, but at chronic treatment, the modulatory effects of dexamethasone aggregated and it augmented the C-fibers reduction anti-inflammatory effect.

On the Polymodal Receptor with Characteristics Suitable for a Receptor that Transmits Acupuncture / Moxibustion Stimuli / 日本東洋医学雑誌

Muscular unmyelinated (C-) fibers are supposed to be the afferent limb of acupuncture effects. Of muscular unmyelinated afferent receptors, polymodal receptors are considered to be important because of their sensitivities to moderate mechanical and strong thermal stimulations and to algesic substances. I would like to introduce response characteristics of muscular polymodal receptors, especially on their sensitization to mechanical stimulation.Polymodal receptors consist of 50% of mechano-sensitive muscular C-fiber receptors in rats. Comparing with non-polymodal receptors that would not respond to heat stimulation, the mechanical threshold of the polymodals is not different, but their discharge rate is lower. The response threshold to heat is around 41°C. The mechanical response of this receptor is augmented by bradykinin, prostaglandins, histamine and acid. Nerve growth factor (NGF) is one of neurotrophic factors that is essential for the development and survival of thin-fiber afferents and their differentiation during ontogeny. In adulthood NGF is produced in inflammatory cells (macrophages, mast cells, etc) and fibroblasts, and sensitizes nociceptors to heat and mechanical stimulations, and plays an important role in hyperalgesia. It is reported that intramuscular injection of NGF into humans induced mechanical hyperalgesia.Recently we found up-regulation of NGF in the muscle in non-inflammatory condition, namely in delayed onset muscle soreness that appears after strenuous and unaccustomed exercise (delayed onset muscle soreness). Up-regulation of NGF in the muscle starts about 12 hrs after exercise, and it lasts up to 2 days after exercise. Anti-NGF antibody injection to the muscle on the 2nd day after exercise, reversed mechanical hyperalgesia. Thus it is concluded that sensitization of C-fiber receptors by NGF to mechanical stimulation results in mechanical hyperalgesia. Because there is no sign of inflammation in the muscle, cells that produce NGF cannot be inflammatory cells, and muscle cells themselves, blood vessel cells or connective tissue cells might produce NGF. In addition, the majority of sensory receptors that are sensitized after exercise are heat sensitive, that means they are mostly polymodal receptors. Because many of muscle pain conditions are not inflammatory, non-inflammatory production of NGF in the muscle observed in the delayed onset muscle soreness raises a possibility that NGF is produced in other muscle pain conditions, and sensitizes muscle nociceptors to result in muscle hyperalgesia. This point must be clarified in future.

Effects of Somatostatin on the Responses of Rostrally Projecting Spinal Dorsal Horn Neurons to Noxious Stimuli in Cats

Somatostatin (SOM) is a widely distributed peptide in the central nervous system and exerts a variety of hormonal and neural actions. Although SOM is assumed to play an important role in spinal nociceptive processing, its exact function remains unclear. In fact, earlier pharmacological studies have provided results that support either a facilitatory or inhibitory role for SOM in nociception. In the current study, the effects of SOM were investigated using anesthetized cats. Specifically, the responses of rostrally projecting spinal dorsal horn neurons (RPSDH neurons) to different kinds of noxious stimuli (i.e., heat, mechanical and cold stimuli) and to the A delta-and C-fiber activation of the sciatic nerve were studied. Iontophoretically applied SOM suppressed the responses of RPSDH neurons to noxious heat and mechanical stimuli as well as to C-fiber activation. Conversely, it enhanced these responses to noxious cold stimulus and A delta-fiber activation. In addition, SOM suppressed glutamate-evoked activities of RPSDH neurons. The effects of SOM were blocked by the SOM receptor antagonist cyclo-SOM. These findings suggest that SOM has a dual effect on the activities of RPSDH neurons; that is, facilitation and inhibition, depending on the modality of pain signaled through them and its action site.

Effects of Spinal Cord Stimulation and Adenosine on Responsiveness of Dorsal Horn Neurons in Neuropathic Rats / 대한마취과학회지

BACKGROUND: The aim of the present study was to investigate the effect of spinal cord stimulation (SCS) on the electrically evoked responses of the dorsal horn neuron. An additional aim was to examine whether adenosine receptor activation is involved in the effects of SCS. METHODS: SCS was performed in a rat with a selective spinal nerve (L5/L6) ligation. Adenosine receptor antagonist, theophylline, was administered intraperitoneally after SCS. Extracellular recordings were made from dorsal horn neurons receiving C- and A-fiber input from the ipsilateral hindpaw. Neuronal responses were elicited by supramaximal electrical stimulation, given in the sciatic nerve. RESULTS: Following intraperitoneal administration of theophylline (50 mg/kg), the decreased C-fiber evoked responses were by SCS suppression restored to a pre-SCS level. SCS and theophylline did not produce any significant change in the A-fiber evoked response. CONCLUSIONS: These results indicate that C-fiber evoked responses are inhibited in preference to A-fiber evoked responses by SCS, and that adenosine-dependent mechanisms may be involved in the resulting SCS effect.

The Effects of Spinal Cord Stimulation on the Spinal Nociceptive Process Evaluated by Cord Dorsum Potential in Cats / 대한마취과학회지

BACKGROUND: The pain-inhibitory effects of spinal cord stimulation (SCS) may be exerted at two alternative or complementary levels, segmentally or supraspinally. However the actual pathways, site of action, and synaptic relays are poorly understood. No data is available which concerns the changes in cord dorsum potential (CDP) associated with a single neuronal level, after SCS. METHODS: SCS was performed in normal and spinalized cats. At the lumbosacral enlargement, CDP and extracellular single cell activity in response to electrical stimulation of Asigma- or C-fiber of the dorsal root or sciatic nerve were recorded. RESULTS: The resulting CDP consisted of characteristic waves of Asigma- and C-fiber with a different time latency. CDP sno significant differences in the amplitude of Asigma- and C-fiber wave between the normal and spinalized cats. In both groups, CDP showed decrease in the amplitude of C-fiber wave. Single cell responses were either increased or decreased after SCS. The C- response changed more marKedly than the A-response in both the normal and spinalized cats. In the bicuculline administered cats, single cell responses increased after SCS, but no change was found in the amplitude of CDP. CONCLUSIONS: The above results might indicate that SCS suppresses C-fiber transmission of nociceptive electrical stimuli via a segmental inhibitory mechanism, and that SCS is more effective in blocKing the transmission of nociceptive electrical stimuli via the C-fiber than Asigma-fiber.

Zn2+ modulates the responses of rat dorsal horn neuron to C-fiber stimulation and excitatory amino acids

Zinc contained in the neurons of central nervous system is activity-dependently released and then attenuates NMDA (N-methyl-D-aspartate)-induced neurotoxicity while augmenting non-NMDA-induced neurodegeneration. Zinc also has been reported to produce antinociceptive action on the inflammation- and nerve injury-induced hyperalgesia in the behavioral test. In this study, we investigated the effects of zinc on the responses of dorsal horn cells to NMDA, kainate and graded electrical stimulation of C-fibers. In the majority of WDR cells (70.6%), zinc current-dependently inhibited WDR cell responses to NMDA and in the remaining cells, produced biphasic responses; excitation followed by inhibition. Zinc augmented the responses of WDR cells to iontophoretical application of kainate. The dominant effect of Zn2+ on the responses of WDR cells to C-fiber stimulation was excitatory, but inhibition, excitation-inhibition and no change of the responses to C-fiber stimulation were induced. Ca2+-EDTA antagonized the excitatory or inhibitory effects of Zn2+ on the WDR cell responses. These experimental findings suggest that Zn2+ modulates the transmission of sensory information in the rat spinal cord.

The role of somatostatin in nociceptive processing of the spinal cord in anesthetized cats

Somatostatin (SOM) is one of the major neuropeptides in dorsal root ganglion cells, but its role in spinal nociceptive process has not been well known. In present study we aimed to investigate the effect of SOM on the response of dorsal horn neurons to the various types of peripheral nociceptive stimuli in anesthetized cats. Using carbon-filament microelectrode, the single cell activities of wide dynamic range neurons were recorded from the lumbosacral enlargement after noxious mechanical (squeeze), thermal (radiant heat lamp) and cold (dry ice) stimulation to the receptive field. Sciatic nerve was stimulated electrically to evoke A delta- and C-nociceptive responses SOM analogue, octreotide (10 mug/kg), was applied intravenously and the results were compared with those of morphine (2 mg/kg, MOR) Systemic SOM decreased the cellular responses to the noxious heat and the mechanical stimulation, but increased those to the cold stimulation. In the responses to the electric stimuli of sciatic nerve, A delta-nociceptive response was increased by SOM, while C-nociceptive response was decreased. On the other hand, MOR inhibited the dorsal horn cell responses to all the noxious stimuli. From the above results, it is concluded that SOM suppresses the transmission of nociceptive heat and mechanical stimuli, especially via C-fiber, while it facilitates those of nociceptive cold stimuli via A delta-fiber.

The Changes in Cord Dorsum Potential after Spinal Cord Stimulation / 대한마취과학회지

BACKGROUND: Spinal cord stimulation(SCS) evolved as a direct clinical application of the famous gate-control theory, the idea of activating the central collaterals of large afferent fibers contained in the dorsal column. It is well known that the cord dorsum potential(CDP) evoked by stimulation of dorsal roots or peripheral nerves can be recorded from the cord surface in spinal animals. However, there have been no data about the changes in CDP after SCS. METHODS: Using ball-type electrode, CDP was recorded at the dorsal root entry zone of lumbosacral enlargement in anesthetized cats. The dorsal root was stimulated electrically to activate Adelta-fiber(single pulse of 0.2 ms duration and 1 mA intensity) and C-fiber(single pulse of 0.2 ms duration and 10 mA intensity). Potentials were averaged 10 times and measured before(control) and immediately after, and 10, 20, 30, 40, 50, 60 min after SCS for 20 min. RESULTS: CDP elicited by dorsal root stimulation consisted of the characteristic waves of Adelta-fiber and C-fiber with different time latency. CDP showed significant decrease in the amplitude of C-fiber wave immediately after SCS(75.0+/-8.8%), and 20 min(69.0+/-7.9%), 30 min(75.1+/-4.4%), 40 min(75.4+/-4.4%), 50 min(78.3+/-5.9%), but not 10 min and 60 min, after SCS. However there were no statistically significant decrease in the amplitude of Adelta-fiber wave after SCS. CONCLUSIONS: The above results indicates that SCS suppresses the transmission of nociceptive electrical stimuli via C-fiber, while SCS has little influence on the transmission of electrical nociceptive stimuli via Adelta-fiber.

Calcium channel blockers suppress the responses of rat dorsal horn cell to nociceptive input

Calcium ions are implicated in a variety of physiological functions, including enzyme activity, membrane excitability, neurotransmitter release, and synaptic transmission, etc. Calcium antagonists have been known to be effective for the treatment of exertional angina and essential hypertension. Selective and nonselective voltage-dependent calcium channel blockers also have inhibitory action on the acute and tonic pain behaviors resulting from thermal stimulation, subcutaneous formalin injection and nerve injury. This study was undertaken to investigate the effects of iontophoretically applied Ca++ and its antagonists on the responses of WDR (wide dynamic range) cells to sensory inputs. The responses of WDR cells to graded electrical stimulation of the afferent nerve and also to thermal stimulation of the receptive field were recorded before and after iontophoretical application of Ca++, EGTA, Mn++, verapamil, omega-conotoxin GVIA, omega-conotoxin MVIIC and omega-agatoxin IVA. Also studied were the effects of a few calcium antagonists on the C-fiber responses of WDR cells sensitized by subcutaneous injection of mustard oil (10%). Calcium ions and calcium channel antagonists (Mn++, verapamil, omega-conotoxin GVIA & omega-agatoxin IVA) current-dependently suppressed the C-fiber responses of WDR cells without any significant effects on the A-fiber responses. But omega-conotoxin MVIIC did not have any inhibitory actions on the responses of WDR cell to A-fiber, C-fiber and thermal stimulation. Iontophoretically applied EGTA augmented the WDR cell responses to C-fiber and thermal stimulations while spinal application of EGTA for about 20 ~ 30 min strongly inhibited the C-fiber responses. The augmenting and the inhibitory actions of EGTA were blocked by calcium ions. The WDR cell responses to thermal stimulation of the receptive field were reduced by imtophoretical application of Ca++, verapamil, omega -agatoxin IVA, and omega-conotoxin GVIA but not by omega-conotoxin MVIIC. The responses of WDR cells to C-fiber stimulation were augmented after subcutaneous injection of mustard oil (10%, 0.15 ml) into the receptive field and these sensitized C-fiber responses were strongly suppressed by iontophoretically applied Ca++, verapamil, omega-conotoxin GVIA and omega-agatoxin IVA. These experimental findings suggest that in the rat spinal cord, L-, N-, and P-type, but not Q-type, voltage-sensitive calcium channels are implicated in the calcium antagonist-induced inhibition of the normal and the sensitized responses of WDR cells to C-fiber and thermal stimulation, and that the suppressive effect of calcium and augmenting action of EGTA on WDR cell responses are due to changes in excitability of the cell.

Protein kinase C is involved in the induction and early- phase maintenance of long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn of adult rats / 中国病理生理杂志

AIM: The role of protein kinase C (PKC) in th e induction and maintenance of spinal long-term potentiation (LTP) was evaluated . METHODS: The C-fiber evoked field potentials were recorded at t he superficial layers of spinal dorsal horn at the lumbar enlargement. RESULTS: (i) Chelerythrine (200 ?mol/L) or G 6983 (100 ? mol/L), a selective PKC inhibitor, completely blocked LTP induction. (ii) Chel eryt hrine or G 6983 reversed spinal LTP in a time-dependent manner. 15 min after L TP induction, chelerythrine (200 ?mol/L) and G 6983 (100 ?mol/L) depre ssed LTP to baseline in all tested rats. The same concentration of chelerythrine and G 6983, applied at 3 h after LTP induction, did not affect LTP. CONCLUSION: PKC in spinal dorsal horn may be crucial for the ind uction and the early-phase maintenance of LTP of C-fiber evoked field potentials .