Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R⁺ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R⁺ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.
Rats ; Animals ; Posterior Horn Cells/pathology* ; Spinal Cord Dorsal Horn/metabolism* ; Neuralgia ; Synaptic Transmission

OBJECTIVETo study on mechanisms of acupuncture in relieving visceral pain.

METHODSIn SD rats CRD was used as noxious visceral stimuli. Activities of spinal dorsal horn wide dynamic (WDR) neurons of L1-L13 were recorded by extracellular microelectrode technique. Acupuncture was given at ipsi-lateral and contra-lateral Zusanli (ST 36) of the same segmental innervation of rectum and colon.

RESULTSVisceral noxious afferent could significantly activate spinal dorsal horn convergent neurons, and mechanical stimulation of contra-lateral body surface and hand acupuncture at Zusanli (ST 36) could inhibit this noxious response. When the spinal cord was acutely blocked, the inhibiting CRD effect of needling CRD effect of needling contra-lateral Zusanli (ST 36) completely disappeared.

CONCLUSIONAcupuncture and visceral noxious afferent signals converge and interact each other in spinal level, and acupuncture at acupoint can inhibit the spinal dorsal horn neuron respon se activated by visceral noxious afferent and this action needs the participation of the center above the spinal cord.

Dopamine has been generally known to exert antinociceptive action in behavioral pain test, such as tail flick and hot plate test, but there appears to be a great variance in the reports on the antinociceptive effect of dopamine depending on the dosage and route of drug administration and type of animal preparation. In the present study, the effects of dopamine on the responses of wide dynamic range (WDR) cells to mechanical, thermal and graded electrical stimuli were investigated, and the dopamine-induced changes in WDR cell responses were compared between animals with an intact spinal cord and the spinal animals. Spinal application of dopamine (1.3 & 2.6 mM) produced a dose-dependent inhibiton of WDR cell responses to afferent inputs, the pinch-induced or the C-fiber evoked responses being more strongly depressed than the brush-induced or the A-fiber evoked responses. The dopamine-induced inhibition was more pronounced in the spinal cat than in the cat with intact spinal cord. The responses of WDR cell to thermal stimulation were also strongly inhibited. Dopamine D2 receptor antagonist, sulpiride, but not D1 receptor antagonist, significantly blocked the inhibitory action of dopamine on the C-fiber and thermal responses of dorsal horn cells. These findings suggest that dopamine strongly suppresses the responses of WDR cells to afferent signals mainly through spinal dopamine D2 receptors and that spinal dopaminergic processes are under the tonic inhibitory action of the descending supraspinal pathways.
Animals ; Cats* ; Dopamine ; Posterior Horn Cells* ; Receptors, Dopamine D2 ; Spinal Cord ; Sulpiride

The present study was undertaken to confirm whether melittin, a major constituent of whole bee venom (WBV), had the ability to produce the same nociceptive responses as those induced by WBV. In the behavioral experiment, changes in mechanical threshold, flinching behaviors and paw thickness (edema) were measured after intraplantar (i.pl.) injection of WBV (0.1 mg & 0.3 mg/paw) and melittin (0.05 mg & 0.15 mg/paw), and intrathecal (i.t.) injection of melittin (6microgram). Also studied were the effects of i.p. (2 mg & 4 mg/kg), i.t. (0.2microgram & 0.4microgram) or i.pl. (0.3 mg) administration of morphine on melittin- induced pain responses. I.pl. injection of melittin at half the dosage of WBV strongly reduced mechanical threshold, and increased flinchings and paw thickness to a similar extent as those induced by WBV. Melittin- and WBV-induced flinchings and changes in mechanical threshold were dose- dependent and had a rapid onset. Paw thickness increased maximally about 1 hr after melittin and WBV treatment. Time-courses of nociceptive responses induced by melittin and WBV were very similar. Melittin-induced decreases in mechanical threshold and flinchings were suppressed by i.p., i.t. or i.pl. injection of morphine. I.t. administration of melittin (6microgram) reduced mechanical threshold of peripheral receptive field and induced flinching behaviors, but did not cause any increase in paw thickness. In the electrophysiological study, i.pl. injection of melittin increased discharge rates of dorsal horn neurons only with C fiber inputs from the peripheral receptive field, which were almost completely blocked by topical application of lidocaine to the sciatic nerve. These findings suggest that pain behaviors induced by WBV are mediated by melittin-induced activation of C afferent fiber, that the melittin- induced pain model is a very useful model for the study of pain, and that melittin-induced nociceptive responses are sensitive to the widely used analgesics, morphine.
Analgesics ; Bee Venoms* ; Bees* ; Lidocaine ; Melitten* ; Morphine ; Nerve Fibers, Unmyelinated ; Nociception ; Posterior Horn Cells ; Sciatic Nerve

Epidural injection of 2-4mg morphine for 7-14 days were given to 18 patients with severe chronic pain. All cases except 2 arachnoiditis had considerable amelioration of pain, which commenced within 2-3min, reached a peak in 10-20min, and was effective for 6-72 hours. Using sensory evoked potentials(SEP) examination for pre-and post-morphine epidural infusion in 18 pain patients, we found the morphine inhibited the action of spinal pain receptor system. It is suggested that morphine reached the subarachnoid space and produced its effect by direct action on the specific opiate receptors in the substantia gelatinosa of the posterior horn cell of the spinal cord.
Arachnoid ; Arachnoiditis ; Chronic Pain* ; Humans ; Injections, Epidural ; Morphine* ; Nociceptors ; Posterior Horn Cells ; Receptors, Opioid ; Spinal Cord ; Subarachnoid Space ; Substantia Gelatinosa

Caudal narcotic analgesia was assessed after the injection of 3mg morphine diluted in 30ml(physiologic) saline into the sacral canal in 15 patients after upper abdominal surgery, in 20 patients after lower abdominal surgery under general anesthesia, and in 20 patients after perianal surgery under caudal block. Pain relief was evaluated by the subsequent need for systemic analgesics. All cases had considerable relief from pain and the morphine was effective for 12 or more hours. There were no significant differences between pain relief of the upper abdominal and lower abdominal surgery group, upper abdomianl and perianal surgery group, and lower abdominal and perianal surgery group (p>0.05, p>0.05, p>0.05). It is suggested that the morphine, which was administered into the sacral, cannal, reached the subarachnoid space and produced it's effect by direct action on the specific opiate receptors in the substantia gelatinosa of the posterior horn cell of the spinal cord. Consequently, whether analgesia from epidural narcotics appears to be segmental in distribution or not is still in controveray.
Analgesia ; Analgesics ; Anesthesia, General ; Humans ; Morphine* ; Narcotics ; Pain, Postoperative* ; Posterior Horn Cells ; Receptors, Opioid ; Spinal Cord ; Subarachnoid Space ; Substantia Gelatinosa

Spinal cord injury often leads to central neuropathic pain syndromes, such as allodynic and hyperalgesic behaviors. Electrophysiologically, spinal dorsal horn neurons show enhanced activity to non-noxious and noxious stimuli as well as increased spontaneous activity following spinal cord injury, which often called hyperexcitability or central sensitization. Under hyperexcitable states, spinal neurons lose their ability of discrimination and encoding somatosensory information followed by abnormal somatosensory recognition to non-noxious and noxious stimuli. In the present review, we summarize a variety of pathophysiological mechanisms of neuronal hyperexcitability for treating or preventing central neuropathic pain syndrome following spinal cord injury.
Animals ; Central Nervous System Sensitization ; Discrimination (Psychology) ; Neuralgia ; Neurons ; Posterior Horn Cells ; Rats ; Spinal Cord ; Spinal Cord Injuries

In this study, we examined the morphine-induced modulation of the nociceptive spinal dorsal horn neuronal activities before and after formalin-induced inflammatory pain. Intradermal injection of formalin induced time-dependent changes in the spontaneous activity of nociceptive dorsal horn neurons. In naive cats before the injection of formalin, iontophoretically applied morphine attenuated the naturally and electrically evoked neuronal responses of dorsal horn neurons. However, neuronal responses after the formalin-induced inflammation were significantly increased by morphine. Bicuculline, GABAA antagonist, increased the naturally and electrically evoked neuronal responses of dorsal horn neurons. This increase in neuronal responses due to bicuculline after the formalin-induced inflammation was larger than that in the naive state, suggesting that basal GABAA tone increased after the formalin injection. Muscimol, GABAA agonist, reduced the neuronal responses before the treatment with formalin, but not after formalin treatment, again indicating an increase in the GABAergic basal tone after the formalin injection which saturated the neuronal responses to GABA agonist. Morphine-induced increase in the spinal nociceptive responses after formalin treatment was inhibited by co-application of muscimol. These data suggest that formalin-induced inflammation increases GABAA basal tone and the inhibition of this augmented GABAA basal tone by morphine results in a paradoxical morphine- induced increase in the spinal nociceptive neuronal responses after the formalin-induced inflammation.
Animals ; Bicuculline ; Cats ; Formaldehyde ; GABA Agonists ; Inflammation ; Injections, Intradermal ; Morphine ; Muscimol ; Neurons ; Nociceptors ; Posterior Horn Cells* ; Spinal Cord

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.
Animals ; Cats* ; Ganglia, Spinal ; Hand ; Hot Temperature ; Microelectrodes ; Morphine ; Neurons ; Neuropeptides ; Octreotide ; Posterior Horn Cells ; Sciatic Nerve ; Somatostatin* ; Spinal Cord*

Magnesium ion is known to selectively block the N-methyl-D-aspartate (NMDA)-induced responses and to have anticonvulsive action, neuroprotective effect and antinociceptive action in the behavioral test. In this study, we investigated the effect of Mg2+ on the responses of dorsal horn neurons to cutaneous thermal stimulation and graded electrical stimulation of afferent nerves as well as to excitatory amino acids and also elucidated whether the actions of Ca2+ and Mg2+ are additive or antagonistic. Mg2+ suppressed the thermal and C-fiber responses of wide dynamic range (WDR) cell without any effect on the A-fiber responses. When Mg2+ was directly applied onto the spinal cord, its inhibitory effect was dependent on the concentration of Mg2+ and duration of application. The NMDA- and kainate-induced responses of WDR cell were suppressed by Mg2+, the NMDA-induced responses being inhibited more strongly. Ca2+ also inhibited the NMDA-induced responses current-dependently. Both inhibitory actions of Mg2+ and Ca2+ were additive, while Mg2+ suppressed the EGTA-induced augmentation of WDR cell responses to NMDA and C-fiber stimulation. Magnesium had dual effects on the spontaneous activities of WDR cell. These experimental findings suggest that Mg2+ is implicated in the modulation of pain in the rat spinal cord by inhibiting the responses of WDR cell to noxious stimuli more strongly than innocuous stimuli.
Animals ; Electric Stimulation ; Excitatory Amino Acids ; Magnesium* ; N-Methylaspartate ; Neuroprotective Agents ; Posterior Horn Cells* ; Rats* ; Spinal Cord