• The Korean Journal of Pain
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• v.11 no.1
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• pp.23-29
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• 1998

Background: The present study was conducted to investigate effects of microinjection of bicuculline, GABA-A receptor antagonist, into the brain stem nuclei on the dorsal horn neuron responsiveness in rats with an experimental peripheral neuropathy. Methods: An experimental neuropathy was induced by a unilateral ligation of L5~L6 spinal nerves of rats. After 2~3 weeks after the surgery, single-unit recording was made from wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Results: Responses of WDR neurons to both noxious and innocuous mechanical stimuli applied to the somatic receptive fields were enhanced on the nerve injured side. These enhanced responsiveness of WDR neurons were suppressed by microinjection of bicuculline into periaqueductal gray(PAG) or nucleus reticularis gigantocellularis(Gi). A similar suppression was also observed when morphine was microinjected into PAG or Gi. Suppressive action by Gi-bicuculline was reversed by naloxonazine, ${\mu}$-opioid receptor antagonist, microinjected into PAG whereas PAG-bicuculline induced suppression was not affected by naloxonazine injection into Gi. Gi-bicuculline induced suppression were reversed by a transection of dorsolateral funiculus(DLF) of the spinal cord. Conclusions: The results suggest that endogenous opioids, via acting on GABAergic interneurons in PAG and Gi, may be involved in the control of neuropathic pain by activating the descending inhibitory pathways that project to the spinal dorsal horn through DLF to inhibit the responsiveness of WDR neurons.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.241-249
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• 1997

The aim of the present study is to examine the brainstem sites where the electrical stimulation produces a suppression of dorsal horn neuron responses of neuropathic rats. An experimental neuropathy was induced by a unilateral ligation of L5-L6 spinal nerves of rats. Ten to 15 days after surgery, the spinal cord was exposed and single-unit recording was made on wide dynamic range (WDR) neurons in the dorsal horn. Neuronal responses to mechanical stimuli applied to somatic receptive fields were examined to see if they were modulated by electrical stimulation of various brainstem sites. Electrical stimulation of periaqueductal gray (PAG), n. raphe magnus (RMg) or n. reticularis gigantocellularis (Gi) significantly suppressed responses of WDR neurons -to both noxious and non-noxious stimuli. Electrical stimulation of other brainstem areas, such as locus coeruleus. (LC) and n. reticularis paragigantocellularis lateralis (LPGi), produced little or no suppression. Microinjection of morphine into PAG, RMg, or Gi also produced a suppression as similar pattern to the case of electrical stimulation, whereas morphine injection into LC or LPGi exerted no effects. The results suggest that PAG, NRM and Gi are the principle brainstem nuclei involved in the descending inhibitory systems responsible for the control of neuropathic pain. These systems are likely activated by endogenous opioids and exert their inhibitory effect by acting on WDR neurons in the spinal cord.

• Korean Journal of Acupuncture
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• v.26 no.2
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• pp.91-108
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• 2009

Objectives: Single colorectal instillation of trinitrobenzenesulphonic acid (TNBS) causes a dose-dependent increase of visceral motor response (VMR) and severity of inflammation. In this study we compared the effects of electroacupuncture in the different acupoints in the acute colitis induced by TNBS intracolonic injection in rats. Methods: In Male Sprague-Dawley rats, weighing $250{\sim}400g$, a single colorectal administration of TNBS 5mg/kg and 50% ethanol under isoflurane anaesthesia after an overnight fast. Electrodes for electromyography (EMG) recording were stitched into the external oblique musculature under general anesthesia. Acupoints of LI4, ST25, or ST36 were stimulated by electroacupuncture, respectively. The balloon was inserted intra-anally and visceral motor response (VMR) to colorectal distensioin (CRD) was quantified with an EMG recording system. Results: At an observation of the visceral hyperalgesia in the day-time series, the visceromotor response increased significantly 3 days after TNBS intra-rectalcolonic injection in rats. Electroacupuncture on either ST25 or ST36 suppressed the visceromotor response to colorectal distension, but not LI4, at 3 days after TNBS injection. Pretreatment of naltrexone (10 mg/kg, i.p.), opioids antagonist, inhibited the VMR suppress of 10Hz EA to ST36 but not phentolamine (5 mg/kg, i.p.). Pretreatment of either naltrexone or phentolamine inhibited effects of 10Hz EA to ST25. Conclusions: Data show that EA at either ST25 or ST36 potently inhibits hypersensitivity of colorectum after TNBS induced colitis and is differently mediated through the endogenous opioid system and adrenergic system.

• The Korean Journal of Pain
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• v.37 no.3
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• pp.211-217
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• 2024

Background: Tolerance to the analgesic effects of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) is a major concern for relieving pain. Thus, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. Biguanide-type drugs such as metformin (MET) are effective for neuroprotection and can be beneficial for addressing opioid tolerance in the treatment of chronic pain. It has been proposed that analgesic tolerance to NSAIDs is mediated by the endogenous opioid system. According to the cross-tolerance between NSAIDs, especially sodium salicylate (SS), and opiates, especially morphine, the objective of this study was to investigate whether MET administration can reduce tolerance to the anti-nociceptive effects of SS. Methods: Fifty-six male Wistar rats were used in this research (weight 200-250 g). For induction of tolerance, SS (300 mg/kg) was injected intraperitoneally for 7 days. During the examination period, animals received MET at doses of 50, 75, or 100 mg/kg for 7 days to evaluate the development of tolerance to the analgesic effect of SS. The hot plate test was used to evaluate the drugs' anti-nociceptive properties. Results: Salicylate injection significantly increased hot plate latency as compared to the control group, but the total analgesic effect of co-treatment with SS + Met50 was stronger than the SS group. Furthermore, the effect of this combination undergoes less analgesic tolerance over time. Conclusions: It can be concluded that MET can reduce the analgesic tolerance that is induced by repeated intraperitoneal injections of SS in Wister rats.

• Korean Journal of Veterinary Research
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• v.38 no.3
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• pp.535-543
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• 1998

In the present study, we designed and constructed new microdialysis probe in order to improve the efficacy and accuracy of microdialysis method. In addition, extracellular concentrations of GABA, glutamate, aspartate and glycine were monitored with new designed probe in the lateral portion of the ventrocaudal periaqueductal gray using unanesthetized and unrestrained rats. Furthermore, the effect of opiates on release of these amino acids, especially GABA, was analyzed by measuring their concentration in PAG dialysates following veratridine administration in the presence of systemic morphine. The results were summerized as follow : 1. The damaging rates of 1.0mm or 1.5mm window probe were 12.5% or 42.8%, respectively. In the group using 1.5mm window probe, the damaging area was extended into mesencephalic aqueduct because of microdialyzing pressure. 2. Because of the unique design of our probes with an opening facing one side, dialysis occurs in a hemisphere($600{\mu}m$ in mediolateral direction and $100{\mu}m$ in opposite side of the dialysis probe) around the opening rather than in a spherical shaped configuration which is typical of most commercially available probe designs. 3. Glutamate, taurine and glycine were present in the highest concentration in the dialysate sample obtained before treatment with veratridine, whereas, aspartate and GABA were present in the lowest concentration. 4. The concentration of all 5 amino acids increased significantly following $75{\mu}m$ veratridine perfusion into lateral ventrocaudal PAG. 5. There was no significant difference between basal and peak amino acid concentrations according to window sizes. 6. Morphine had no effect on baseline concentrations of amino acids in dialysates obtained from the lateral PAG as compared to saline treated controls. However, following veratridine treatment, morphine selectively affected GABA release in the lateral ventrocaudal PAG as compared to saline treated controls. These results suggest that GABAergic interneurons in the PAG are inhibited by opioids. Therefore, endogenous enkephalins or endorphins may directly inhibit intrinsic GABAergic intemeurons and block their tonic inhibition of PAG-NMR projection neurons. Moreover, new designed probes demonstrate improved efficiency and accuracy in collecting samples as compared to commercial types of microdialysis probes.

• The Korean Journal of Pharmacology
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• v.23 no.2
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• pp.57-75
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• 1987

Two modalities of gonadotropin secretion, pulsatile gonadotropin and preovulatory gonadotropin surge, have been identified in the mammals. Pulsatile gonadotropin secretion is modulated by the pulsatile pattern of GnRH release and complex ovarian steroid feedback actions. The neural mechansim that regulates the pulsatile release of GnRH in the hypothalamus is called "GnRH pulse generator". Ovarian steroids, estradiol and progesterone, appear to exert thier feedback effects both directly on the pituitary to modulate gonadotropin release and on a hypothalamic site to modulate GnRH release; estradiol primarily affects the amplitude while progesterone decreases the frequency of the pulsatile GnRH. Steroid hormones are known to affect catecholamine transmission in brain. MBH-POA is richly innervated by NE systems and close apposition of NE terminals and GnRH cell bodies occurs in the MBH as well as in the POA. NE normally facilitates pulsatile LH release by acting through ${\alpha}-receptor$ mechanism. However, precise nature of facilitative role of NE transmission in maintaining pulsatile LH has not been clearly understood. Close apposition of DA and GnRH terminals in ME might permit DA to influence GnRH release. Action of DA transmission probably is mediated by axo-axonic contacts between GnRH and DA fibers in the ME. Dopamine transmission does not normally regulate pulsatile LH release, but under certain conditions, increased DA transmission inhibit LH pulse. Endogenous opioid acts to suppress the secretion of GnRH into hypophysial portal circulation, thereby inhibiting gonadotropin secretion. However, an interaction between endogenenous opioid peptides and gonadotropin release is a complex one which involves ovarian hormones as well. LH secretion appears to be most suppressed by endogenenous opioids during the luteal phase, at a time of elevated progesterone secretion. The arcuate nucleus contains not only cell bodies for GnRH and ${\beta}-endorphin$ but also a dense aborization of fibers suggesting that GnRH release is changed by the interactions between GnRH and ${\beta}-endorphin$ cell bodies within the arcuate nucleus. The frequency and amplitude of pulsatile LH release seem to be increased during the preovulatory gonadotropin surge. Estradiol exerts positive feedback action on the hypothalamo-pituitary axis to trigger preovulatory LH surge. GnRH is also crucial hormonal stimulus for preovulatory LH surge. It is unlikely, however, that increased secretion of GnRH during the preovulatory gonadotropin surge represents an obligatory neural signal for generation of the LH discharge in primates including human. Modulation of preovulatory LH surge by catecholamines has been studied almost exclusively in rats. NE and E may be involved in distinct way to accumulate GnRH in the MBH and its release into the hypophysial portal system during the critical period for LH surge on proestrus in rats. However, the mechanisms whereby augmented adrenergic transmission may facilitate the formation and accumulation of GnRH in the ME-ARC nerve terminals before the LH surge have not been clearly understood.