• 약학회지
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• 제43권4호
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• pp.411-418
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• 1999

Intracerebroventricular (ICV) infusion of morphine (MOR) produces strong analgesia in man and animals. The analgesic effect is thought to be mediated by the centrifugal inhibitory control. But neural mechanisms of the analgesic effect of ICV morphine are not well understood. In the present study, we found that ICV MOR had dual actions on the activity of dorsal horn heurons: it produced both inhibition and excitation of dorsal horn neurons. Since MOR exerts its action via three different types of opioid receptors, we further sought to investigate if there are differential effects of opioid receptor agonists on dorsal horn neurons when administered intracerebroventricularly. Effects of ICV MOR were tested in 28 dorsal horn neurons of the spinal cord in the cat. ICV MOR inhibited, excited and did not affect the heat responses of dorsal horn neurons. ICV DAMGO and DADLE, $\mu$- and $\delta$-opioid agonist, respectively, exhibited the excitation of dorsal horn neurons. In contract, U-50488, a k-opioid agonist, exhibited both the inhibition and excitation of dorsal horn neurons. These results suggest that opioid receptors have different actions on activity of dorsal horn neuron and that the inhibitory action of k-opioid agonist may subserve the analgesia often produced by ICV MOR.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.303-303
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• 1994

ICV infusion of morphine (MOR) produces strong analgesia in man and animals. The analgesic effect is thought to be mediated by the centrifugal inhibtory control, But neural mechanisms of the analgesic effect of ICV morphine are not well understood. For example, in the previous studies, ICV morphine does not inhibit nociceptive transmission in the spinal cord. On the contrary, ICV MOR often excites activity of dorsal horn neuron in the spinal cord. In the present study, we found that ICV MOR had dust actions on activity of dorsal horn neuron that it produced both inhibition and excitation of dorsal horn neurons. Since MOR exerts i Is action via three different types of opioid receptors, we further sought to investigate if there are differential effects of opioid receptor agonists on dorsal horn neurons when administered ICV.

• The Korean Journal of Pain
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• 제13권1호
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• pp.19-30
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• 2000

Background: Partial nerve injury to a peripheral nerve may induce the development of neuropathic pain which is characterized by symptoms such as spontaneous burning pain, allodynia and hyperalgesia. Though underlying mechanism has not fully understood, sensitization of dorsal horn neurons may contribute to generate such symptoms. Nitric oxide acts as an inter- and intracellular messenger in the nervous system and is produced from L-arginine by nitric oxide synthase (NOS). Evidence is accumulating which indicate that nitric oxide may mediate nociceptive information transmission. Recently, it has been reported that NOS inhibitor suppresses neuropathic pain behavior in an neuropathic pain animal model. This study was conducted to determine whether nitric oxide could be involved in the sensitization of dorsal horn neurons in neuropathic animal model. Methods: Neuropathic animal model was made by tightly ligating the left L5 and L6 spinal nerves and we examined the effects of iontophoretically applied NOS inhibitor (L-NAME) on the dorsal horn neuron's responses to mechanical stimuli within the receptive fields. Results: In normal animals, NOS inhibitor (L-NAME) specifically suppressed the responses to the noxious mechanical stimuli. In neuropathic animals, the dorsal horn neuron's responses to mechanical stimuli were enhanced and NOS inhibitor suppressed the dorsal horn neuron's enhanced responses to non-noxious stimuli as well as those to noxious ones. Conclusions: These results suggest that nitric oxide may mediate nociceptive transmission in normal animal and also mediate sensitization of dorsal horn neurons in neuropathic pain state.

• Journal of Korean Neurosurgical Society
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• 제29권7호
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• pp.877-885
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• 2000

Objective : The NOS inhibitors exhibit antinociceptive activity in rat model of neuropathic pain. NOS activity increases in the dorsal root ganglia(DRG) in neurop-athic pain. However, NOS activity decreases in the dorsal horn of spinal cord in the nerve injury models of neuropathic pain. To investigate whether the mechanism of decrease of NOS expression in the dorsal horn is related to a secondary effect resulting from increased NO production and likewise in the spinal DRG in the spinal nerve ligation model of neuropathic pain. Methods : We conducted behavioral tests for neuropathic pain, and nNOS immunohistochemistry and NADPH-diaphorase histochemistry after tight ligation of the 5th lumbar(L5) and 6th lumbar(L6) spinal nerves and L5 dorsal rhizotomy. Results : Typical neuropathic pain behaviors occurred 7 days after post-ligation in the neuropathic surgery group, but neuropathic pain behaviors in the dorsal rhizotomy group were absent or weak 7 days after post-operation. There was a decrease in the number of nNOS immunoreactive dorsal horn neurons on the both side(especially ipsilateral side) 7 days after post-ligation. The number of nNOS immunoreactive neurons in both side of the dorsal horn was not decreased 7 days after L5 dorsal rhizotomy. Conclusion : These data indicate that the changes in the injured DRG is essential for development and maintenance of neuropathic pain, and mechanism of decrease of nNOS expression in the dorsal horn is a secondary effect against the changes in the DRG including increased NO production in the spinal nerve ligation model of neuropathic pain.

• The Korean Journal of Pain
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• 제19권1호
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• pp.22-32
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• 2006

Background: This study was conducted to investigate the roles of the spinal and peripheral ${\gamma}$-aminobutyric acid (GABA)- ergic systems for the mechanical hypersensitivity produced by chronic compression of the dorsal root ganglion (CCD). Methods: CCD was performed at the left 5th lumbar dorsal root ganglion. The paw withdrawal threshold (PWT) to von Frey stimuli was measured. The mechanical responsiveness of the lumbar dorsal horn neurons was examined. GABAergic drugs were delivered with intrathecal (i.t.) or intraplantar (i.pl.) injection or by topical application onto the spinal cord. Results: CCD produced mechanical hypersensitivity, which was evidenced by the decrease of the PWT, and it lasting for 10 weeks. For the rats showing mechanical hypersensitivity, the mechanical responsiveness of the lumbar dorsal horn neurons was enhanced. A similar increase was observed with the normal lumbar dorsal horn neurons when the GABA-A receptor antagonist bicuculline was topically applied. An i.t. injection of GABA-A or GABA-B receptor agonist, muscimol or baclofen, alleviated the CCD-induced hypersensitivity. Topical application of same drugs attenuated the CCD-induced enhanced mechanical responsiveness of the lumbar dorsal horn neurons. CCD-induced hypersensitivity was also improved by low-dose muscimol applied (i.pl.) into the affected hind paw, whereas no effects could be observed with high-dose muscimol or baclofen. Conclusions: The results suggest that the neuropathic pain associated with compression of the dorsal root ganglion is caused by hyperexcitability of the dorsal horn neurons due to a loss of spinal GABAergic inhibition. Peripheral application of low-dose GABA-A receptor agonist can be useful to treat this pain.

• Restorative Dentistry and Endodontics
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• 제19권2호
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• pp.621-632
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• 1994

This experiment was performed to study the effect of capsaicin on the excitatory amino acids (EAAs) neurotransmitter in medullary dorsal horn and to clarify the relationship between substance P and excitatory amino acids. Horizontal slice of rat medullary dorsal horn was prepared and perfused with modified Krebs-Ringer solution in brain slice chamber. Release of EAAs was induced by veratrine and capsaicin were added to perfusion solution to observe the changes in EAA release. Capsaicin and ruthenium red, capsaicin antagonist, were also systemically injected with 50mg/kg in first day and 100mg/kg in second day for 2 days. Medulla oblongata containing the medullary dorsal horn was isolated, homogenized and centrifused. Spernatant was freeze-dried and EAA was determined by HPLC. Release of glutamate and aspartate was significantly increased by veratrine or capsaicin, but veratrine evoked release of EAAs was blocked by capsaicin in vitro, and injected ruthenium red did not have effect on the contents of EMs in vivo. Systemically injected capsaicin evoked the slight decrease in content of glutamate and aspartate in medullary dorsal horn and this effect of capsaicin was unaffected by ruthenium red.

• 약학회지
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• 제43권3호
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• pp.404-410
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• 1999

Administration of capsaicin produces acute pain and subsequent long-lasting antinociception. The antinociceptive action site of capsaicin is primarily small afferent nerve fibers. However, the effect of capsaicin on the neural activity of dorsal horn neurons are not well understood. The goal of the present experiment was to study the action of capsaicin on activity of dorsal horn neurons using c-fos immunoreactivity in the spinal cord. Intradermal injection of formalin in the hindpaw produced inflammation in the foot pad and increased the number of cells exhibiting Fos-like immunoreactivity (FLI) in the dorsal horn of the spinal cord, suggesting the hyperalgesia because of the apparent inflammation. Intradermal injection of capsaicin prior to formalin injection significantly reduced the number of cells exhibiting FLI induced by formalin and increased the paw-withdrawal latency, suggesting the hypoalgesic effect of capsaicin. Coadministeration with capsaicin of capsazepine and ruthenium red, antagonists of capsaicin receptor reversed the reduction of formalin-induced FLI by capsaicin. he antagonists also partially antagonized the antinociceptive effect of capsaicin in the paw-withdrawal test. These results further suggest that capsaicin reduces prsponses of dorsal horn neurons to the inflammatory nociceptive stimuli in the periphery. Thus, the reduction of FLI subserves the neural mechanisms underlying analgesia produced by capsaicin.

• The Korean Journal of Physiology and Pharmacology
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• 제9권2호
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• pp.77-86
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• 2005

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, $GABA_A$ 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 $GABA_A$ tone increased after the formalin injection. Muscimol, $GABA_A$ 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 $GABA_A$ basal tone and the inhibition of this augmented $GABA_A$ basal tone by morphine results in a paradoxical morphineinduced increase in the spinal nociceptive neuronal responses after the formalin-induced inflammation.

• 대한물리치료과학회지
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• 제7권2호
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• pp.545-558
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• 2000

The present study was designed to investigate the effect of low power GaAsAl laser on Fos expression in the spinal cord induced by noxious mechanical stimulation. Noxious mechanical stimulation was applied to the right hind paw following 30min of low power laser treatment using different intensity and treatment point and the resulting Fos expression in the spinal cord dorsal horn was compared to that obtained in rats exposed only to the noxious mechanical stimulation. The results were summarized as follows: 1. In intact control rats, only a few Fos like immunoreactive(Fos-IR) neurons were evident in the lumbar spinal cord dorsal horn. Similarly, following prolonged inhalation anesthesia, Fos-IR neurons were absent in the dorsal horn of the lumbar spinal cord. In animals treated with noxious mechanical stimulation, neurons with nuclei exhibiting Fos immunostaining were distributied mainly in the medial half of ipsilateral laminae I-V at lumbar segments L3-5. These findings directly indicated that prolonged anesthesia used in this study did not affect the Fos expression in the spinal cord dorsal horn of intact animals and noxious mechanical stimulation treated animals. 2. In acupoint treated animals, 10mW of laser stimulation, not 3mW intensity, significantly reduced the number of Fos immunoreactive neurons in the spinal dorsal horn induced by noxious mechanical stimulation(P<.01). However, the supressive effect of low power laser stimulatin was not observed in 3m Wand 10m W of laser stimulation into non-acupoint. These data indicate that 10mW of low power laser stimulation into acupoint is capable of inhibiting the expression of Fos in the dorsal horn induced by noxious mechanical stimulation. In conclusion, these findings raise the possibility that low power laser stimulation into acupoint may be a promising alternative medicine therapy for the mechanical stimulation induced pain in the clinical field.

• 동의생리병리학회지
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• 제19권3호
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• pp.749-752
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• 2005

We investigated the effects of electroacupuncture (EA) on the expression of cyclooxygenase in the spinal cord of acute inflammatory pain model. Inflammation was induced by an intraplantar injection of 1% carrageenan into the right hind paw of Sprague-Dawley. Bilateral 2 Hz EA stimulation with 0.5 mA, 1 mA and 3 mA were delivered at those acupoints corresponding to Zusanli and Sanyinjiao in man via the needles in carrageenan-injected rats. Three hours after carrageenan injection, effects of EA on cyclooxygenase (COX) expression were observed in the dorsal horn of the spinal cord using immunohistochemical method. The immunoreaction of COX-1 tended to increase in the superficial laminae and the neck of the dorsal horn as compared with normal. The COX-2 immunoreaction in the carrageenan-injected rat was also significantly increased in the all regions of the dorsal horn as compared with normal one. However, COX-1 immunoreaction in carrageenan-injected rat were decreased in the superficial laminae and neck of the dorsal horn by low intensity of EA stimulation. Except high intensity of EA stimulation in the superficial laminae, COX-2 expression was attenuated in all regions of the dorsal horn by all types of EA treatment. It is concluded that EA treatment may attenuate inflammatory pain in carrageenan-injected rat through modulating expression of COX-2 in the dorsal horn of the spinal cord.