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.

Animals ; Colon ; innervation ; Nociceptors ; Posterior Horn Cells ; Rats, Sprague-Dawley ; Rectum ; 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

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

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

OBJECTIVETo study the encoding information of electrical signals of wide dynamic range (WDR) neurons in the spinal dorsal horn evoked by acupuncture manipulation at different frequencies using nonlinear dynamics analysis.

METHODSMicroelectrode extracellular recordings were used to observe the WDR neuron discharge evoked by acupuncture manipulation at Zusanli point (ST36) with different frequencies (0.5, 1, 2, and 3 Hz) in SD rats. The nonlinear dynamics analysis method was used to extract the nonlinear characteristic parameters, such as interspike interval, the Lyapunov exponent, Lempel-Ziv complexity, and the neural coding of the electrical signal evoked by acupuncture manipulations at different frequencies.

RESULTSDifferent characteristics were manifested with acupuncture manipulations at 4 different frequencies. More than a simple linear correlation was shown between the firing rate of the WDR neurons and the frequency of the acupuncture manipulation. The electrical signals evoked by acupuncture manipulation at Zusanli point (ST36) showed distinguished chaotic features.

CONCLUSIONSIt is applicable and feasible to describe and summarize the rhythm of the acupuncture electrical signal using the concepts and terminology of the nonlinear dynamics. Different acupuncture manipulation methods could interfere the transmission, coding, and processing of electrical signals in the spinal dorsal horn.

Acupuncture Therapy ; methods ; Animals ; Male ; Microelectrodes ; Nonlinear Dynamics ; Posterior Horn Cells ; physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; physiology

Long-term potentiation (LTP) of C-fiber evoked field potentials in spinal dorsal horn is first reported in 1995. Since then, the mechanisms underlying the long-lasting enhancement in synaptic transmission between primary afferent C-fibers and neurons in spinal dorsal horn have been investigated by different laboratories. In this article, the related data were summarized and discussed.
Animals ; Evoked Potentials ; Long-Term Potentiation ; Nerve Fibers, Unmyelinated ; physiology ; Posterior Horn Cells ; cytology ; Rats, Sprague-Dawley ; Synaptic Transmission

Pain associated with cancer that metastasizes to bone is often severe and debilitating. A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments. In this study, we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons. Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons. Responses of WDR and HT neurons evoked by mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice. Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR neurons in tumor-bearing mice exhibited an increase in spontaneous activity, and enhanced responses to mechanical, heat, and cold stimuli as compared to controls. Our findings show that sensitization of WDR neurons, but not HT neurons, contributes to tumor-evoked hyperalgesia.
Animals ; Disease Models, Animal ; Hyperalgesia ; physiopathology ; Mice ; Neoplasms ; physiopathology ; Pain ; physiopathology ; Posterior Horn Cells ; cytology ; Rats, Sprague-Dawley