• 약학회지
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• 제43권2호
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• pp.263-273
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• 1999

When glutamate was infected intrathecally, the result is similar to those produced by TPA injected. The involvement of protein kinase C (PKC) in the nociceptive responses in rat dorsal horn neurons of lumbar spinal cord was studied. In test with formalin, a PKC inhibitor (chelerythrine) inhibited dose-dependently the formalin-induced behavior response. Neomycin also inhibited it significantly. But, a PKC activator (12-O-tetradecanoylphorbol-13-ester, TPA) showed reverse effect. When gluatamate was injected intrathecally, we observed the result is smilar to those produced by TPA injection. On the other hand, intrathecal injection of glutamate induced thermal and mechanical hyperalgesia. In Tail-flick test, we examined the involvement of PKC on the glutamate-indeced thermal hyperalgesia. Chelerythrine showed an inhibitory effect and TPA enhanced thermal response. Glutamate decreased the mechanical threshold significantly. A pretreatment of chelerythrine and neomycin inhibited glutamate-induced mechanical hyperalgesia, but the effect of neomycin was not significant. TPA had little effect on the mechanical nociceptive response. These results suggest that the PKC activation through metabotropic receptor at postsynaptic region of spinal cord dorsal horn neurons may influence on the persistent nociception produced by chemical stimulation with formalin, thermal and mechanical hyperalgesia induced by glutamate.

• Archives of Pharmacal Research
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• 제28권5호
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• pp.582-586
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• 2005

The present study was designed to characterize the possible roles of spinally located cholera toxin (CTX)- and pertussis toxin (PTX)-sensitive G-proteins in pro- inflammatory cy tokine induced pain behaviors. Intrathecal injection of tumor necrosis factor-a (TNF-${\alpha}$; 100 pg), interleukin-1${\beta}$ (IL-1${\beta}$ 100 pg) and interferon-${\gamma}$ (INF-${\gamma}$; 100 pg) showed pain behavior. Intrathecal pretreatment with CTX (0.05, 0.1 and 0.5 mg) attenuated pain behavior induced by TNF-${\alpha}$ and INF-${\gamma}$ administered intrathecally. But intrathecal pretreatment with CTX (0.05, 0.1 and 0.5${\mu}g$) did not attenuate pain behavior induced by IL-1${\beta}$. On the other hand, intrathecal pretreatment with PTX further increased the pain behavior induced by TNF-${\alpha}$ and IL-1${\beta}$ administered intrathecally, especially at the dose of 0.5 ${\mu}g$. But intrathecal pretreatment with PTX did not affect pain behavior induced by INF-${\gamma}$. Our results suggest that, at the spinal cord level, CTX- and PTX-sensitive G-proteins appear to play important roles in modulating pain behavior induced by pro-inflammatory cytokines administered spinally. Furthermore, TNF-${\alpha}$, IL-1${\beta}$ arid INF-${\gamma}$ administered spinally appear to produce pain behavior by different mechanisms.

• The Korean Journal of Pain
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• 제13권2호
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• pp.259-262
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• 2000

There are many difficulties in the management of terminal cancer pain. We often encounter difficulties when nerve blocks or epidural injection of drugs do not produce good results. Local anesthetics, opioids and adjunctives, were administered to two patients intrathecally. The results were very satisfactory. It has complications such as hypotension or infection due to intrathecal route. In the first case, the pancreatic cancer patient complicated with severe epigastic pain but unfortunately no management was effective in pain control. Intrathecal injection of bupivacaine and morphine mixture was successful even if syncope which was relieved by bed rest. In the second case, the patient complicated with lower abdominal pain due to ovarian cancer who very well controlled by epidural injection of morphine and clonidine mixture but morphine demand was greatly increased. Intrathecal injection of morphine and ketamine were tried. The patient had comportable analgesic effect. CSF leakage to subcutaneous occurred but resolved by change of the catheter position or retunnelling. There were no significant complications reported in two cases.

• Archives of Pharmacal Research
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• 제28권2호
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• pp.209-215
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• 2005

The antinociceptive effect of nicotine administered intracereboventricularly (i.c.v.) or intrathecally (i.t) in several pain models was examined in the present study. We found that i.t. treatment with nicotine (from 5 to 20 g) dose-dependently blocked pain behavior revealed during the second phase, but not during the first phase in the formalin test. In addition, i.c.v. treatment with nicotine (from 0.1 to $10\;{\mu}g$) dose-dependently attenuated pain behavior revealed during both the first and second phases. In addition to the formalin test, nicotine administered i.c.v. or i.t. attenuated acetic acid-induced writhing response. Furthermore, i.c.v. or i.t. administration of nicotine did not cause licking, scratching and biting responses induced by substance P, glutamate, TNF-${\alpha}$(100 pg), IL-$1{\beta}$(100 pg) and INF-${\gamma}$ (100 pg) injectied i.t. The antinociception induced by supraspinally-administered nicotine appears to be more effective than that resulting from spinally administered nicotine. Our results suggest that nicotine administration induces antinociception by acting on the central nervous system and has differing antinociceptive profiles according to the various pain models.

• The Korean Journal of Pain
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• 제18권2호
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• pp.107-112
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• 2005

Background: Nerve ligation injury may produce mechanical allodynia, but this can be reversed after an intrathecal administration of adenosine analogues. In many animal and human studies, ATP-sensitive potassium channel blockers have been known to reverse the antinociceptive effect of various drugs. This study was performed to evaluate the mechanical antiallodynic effects of spinal R-PIA (Adenosine A1 receptor agonist) and the reversal of these effects due to pretreatment with glibenclamide (ATP-sensitive potassium channel blocker). Thus, the relationship between the antiallodynic effects of R-PIA and ATP-sensitive potassium channel were investigated in a neuropathic model. Methods: Male Sprague Dawley rats were prepared by tightly ligating the left lumbar 5th and 6th spinal nerves and implantation of a chronic lumbar intrathecal catheter for drug administration. The mechanical allodynia was measured by applying von Frey filaments ipsilateral to the lesioned hind paw. And the thresholds for paw withdrawal assessed. In study 1, either R-PIA (0.5, 1 and $2{\mu}g$) or saline were administered intrathecally for the examination of the antiallodynic effect of R-PIA. In study 2, glibenclamide (2, 5, 10 and 20 nM) was administered intrathecally 5 min prior to an R-PIA injection for investigation of the reversal of the antiallodynic effects of R-PIA. Results: The antiallodynic effect of R-PIA was produced in a dose dependent manner. In study 1, the paw withdrawal threshold was significantly increased with $2{\mu}g$ R-PIA (P < 0.05). In study 2, the paw withdrawal threshold with $2{\mu}g$ R-PIA was significantly decreased almost dose dependently by intrathecal pretreatment of 5, 10 and 20 nM glibenclamide (P < 0.05). Conclusions: These results demonstrated that an intrathecal injection of ATP-sensitive potassium channel blockers prior to an intrathecal injection of adenosine A1 receptors agonist had an antagonistic effect on R-PIA induced antiallodynia. The results suggest that the mechanism of mechanical antiallodynia, as induced by an intrathecal injection of R-PIA, may involve the ATP-sensitive potassium channel at both the spinal and supraspinal level in a rat nerve ligation injury model.

• The Korean Journal of Physiology and Pharmacology
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• 제9권3호
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• pp.179-186
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• 2005

Whole bee venom (WBV) and its major component, melittin, have been reported to induce long-lasting spontaneous flinchings and hyperalgesia. The current study was designed to elucidate the peripheral and spinal mechanisms of N-methyl-D-aspartate (NMDA) and non-NMDA receptors by which intraplantar (i.pl.) injection of WBV and melittin induced nociceptive responses. Changes in mechanical threshold and flinching behaviors were measured after the injection of WBV (0.04 mg or 0.1 mg/paw) and melittin (0.02 mg or 0.05 mg/paw) into the mid-plantar area of a rat hindpaw. MK-801 and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione disodium) were administered intrathecally (i.t. $10{\mu}g$) or i.pl.($15{\mu}g$) 15 min before or i.t. 60 min after i.pl. WBV and melittin injection. Intrathecal pre- and postadministration of MK-801 and CNQX significantly attenuated the ability of high dose WBV and melittin to reduce paw withdrawal threshold (PWT). In the rat injected with low dose, but not high dose, of WBV and melittin, i.pl. injection of MK-801 effectively suppressed the decrease of PWTs only at the later time-points, but the inhibitory effect of CNQX (i.pl.) was significant at all time-point after the injection of low dose melittin. High dose WBV- and melittin-induced spontaneous flinchings were significantly suppressed by i.t. administration of MK-801 and CNQX, and low dose WBV- and melittin-induced flinchings were significantly reduced only by intraplantarly administered CNQX, but not by MK-801. These experimental flinchings suggest that spinal, and partial peripheral mechanisms of NMDA and non-NMDA receptors are involved in the development and maintenance of WBV- and melittin-induced nociceptive responses.

• The Korean Journal of Pain
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• 제36권4호
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• pp.441-449
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• 2023

Background: Hypertonic saline is used for treating chronic pain; however, clinical studies that aid in optimizing therapeutic protocols are lacking. We aimed to determine the concentration of intrathecally injected hypertonic saline at which the effect reaches its peak as well as the underlying γ-aminobutyric acid (GABA) receptor-related antinociceptive mechanism. Methods: Spinal nerve ligation (SNL; left L5 and L6) was performed to induce neuropathic pain in rats weighing 250-300 g. Experiment 1: one week after implanting the intrathecal catheter, 60 rats were assigned randomly to intrathecal injection with 0.45%, 0.9%, 2.5%, 5%, 10%, and 20% NaCl, followed by behavioral testing at baseline and after 30 minutes, 2 hours, 1 day, and 1 week to determine the minimal concentration which produced maximal analgesia. Experiment 2: after determining the optimal intrathecal hypertonic saline concentration, 60 rats were randomly divided into four groups: Sham, hypertonic saline without pretreatment, and hypertonic saline after pretreatment with one of two GABA receptor antagonists (GABA_A [bicuculline], or GABA_B [phaclofen]). Behavioral tests were performed at weeks 1 and 3 following each treatment. Results: Hypertonic saline at concentrations greater than 5% alleviated SNL-induced mechanical allodynia and had a significant therapeutic effect, while showing a partial time- and dose-dependent antinociceptive effect on thermal and cold hyperalgesia. However, pretreatment with GABA receptor antagonists inhibited the antinociceptive effect of 5% NaCl. Conclusions: This study indicates that the optimal concentration of hypertonic saline for controlling mechanical allodynia in neuropathic pain is 5%, and that its analgesic effect is related to GABA_A and GABA_B receptors.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.647-655
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• 1997

The purpose of present study is to investigate the influence of a spinal gamma-aminobutyric acid B($GABA_B$) receptor on a central regulation of blood pressure(BP) and heart rate(HR), and to define its mechanism in the spinal cord. In urethane-anesthetized, d-tubocurarine-paralyzed and artificially ventilated male Sprague-Dawley rats, intrathecal administration of drugs were carried out using injection cannula(33-gauge stainless steel) through the guide cannula(PE 10) which was inserted intrathecally at lower thoracic level through the puncture of a atlantooccipital membrane. Intrathecal injection of an $GABA_B$ receptor agonist, baclofen(30, 60, 100 nmol) decreased both BP and HR dose-dependently. Pretreatment with 8-bromo-cAMP(50 nmol), a cAMP analog, or glipizide(50 nmol), a ATP-sensitive $K^+$ channel blocker, attenuated the depressor and bradycardic effects of baclofen(100 nmol), but not with 8-bromo-cGMP(50 nmol), a cGMP analog. These results suggest that the $GABA_B$ receptor in the spinal cord plays an inhibitory role in central cardiovascular regulation and that this depressor and bradycardic actions are mediated by the decrease of cAMP via the inhibition of adenylate cyclase and the opening of $K^+$ channel.

• The Korean Journal of Physiology and Pharmacology
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• 제12권5호
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• pp.237-243
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• 2008

Intraplantar injection of melittin has been known to induce sustained decrease of mechanical threshold and increase of spontaneous flinchings. The present study was undertaken to investigate how the melittin-induced nociceptive responses were modulated by changes of metabotropic glutamate receptor (mGluR) activity. Changes in paw withdrawal threshold (PWT), number of flinchings and paw thickness were measured at a given time point after injection of melittin ($10{\mu}g$/paw) into the mid-plantar area of rat hindpaw. To observe the effects of mGluRs on the melittin-induced nociceptions, group I mGluR (AIDA, $100{\mu}g$ and $200{\mu}g$), $mGluR_1$ (LY367385, $50{\mu}g$ and $100{\mu}g$) and $mGluR_5$ (MPEP, $200{\mu}g$ and $300{\mu}g$) antagonists, group II (APDC, $100{\mu}g$ and $200{\mu}g$) and III (L-SOP, $100{\mu}g$ and $200{\mu}g$) agonists were intrathecally administered 20 min before melittin injection. Intraplantar injection of melittin induced a sustained decrease of mechanical threshold, spontaneous flinchings and edema. The effects of melittin to reduce mechanical threshold and to induce spontaneous flinchings were significantly suppressed following intrathecal pre-administration of group I mGluR, $mGluR_1$ and $mGluR_5$ antagonists, group II and III mGluR agonists. Group I mGluR antagonists and group II and III mGluR agonists had no significant effect on melittin-induced edema. These experimental findings indicate that multiple spinal mGluRs are involved in the modulation of melittin-induced nociceptive responses.

• The Korean Journal of Pain
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• 제20권2호
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• pp.92-99
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• 2007

Background: A correlation between a T-type voltage activated calcium channel (VACC) and pain mechanism has not yet been established. The purpose of this study is to find out the effect of ethosuximide and mibefradil, representative selective T-type VACC blockers on postoperative pain using an incisional pain model of rats. Methods: After performing a plantar incision, rats were stabilized on plastic mesh for 2 hours. Then, the rats were injected with ethosuximide or mibefradil, intraperitoneally and intrathecally. The level of withdrawal threshold to the von Frey filament near the incision site was determined and the dose response curves were obtained. Results: After an intraperitoneal ethosuximide or mibefradil injection, the dose-response curve showed a dose-dependent increase of the threshold in a withdrawal reaction. After an intrathecal injection of ethosuximide, the threshold of a withdrawal reaction to mechanical stimulation increased and the increase was dose-dependent. After an intrathecal injection of mibefradil, no change occurred in either the threshold of a withdrawal reaction to mechanical stimulation or a dose-response curve. Conclusions: The T-type VACC blockers in a rat model of postoperative pain showed the antihyperalgesic effect. This effect might be due to blockade of T-type VACC, which was distributed in the peripheral nociceptors or at the supraspinal level. Further studies of the effect of T-type VACC on a pain transmission mechanism at the spinal cord level would be needed.