• The Korean Journal of Physiology and Pharmacology
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• 제13권5호
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• pp.379-383
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• 2009

Nitric oxide (NO), a diffusible gas, is produced in the central nervous system, including the spinal cord dorsal horn and the trigeminal nucleus, the first central areas processing nociceptive information from periphery. In the spinal cord, it has been demonstrated that NO acts as pronociceptive or antinociceptive mediators, apparently in a concentration-dependent manner. However, the central role of NO in the trigeminal nucleus remains uncertain in support of processing the orofacial nociception. Thus, we here investigated the central role of NO in formalin (3%)-induced orofacial pain in rats by administering membrane-permeable or -impermeable inhibitors, relating to the NO signaling pathways, into intracisternal space. The intracisternal pretreatments with the NO synthase inhibitor L-NAME, the NO-sensitive guanylate cyclase inhibitor ODQ, and the protein kinase C inhibitor GF109203X, all of which are permeable to the cell membrane, significantly reduced the formalin-induced pain, whereas the membrane-impermeable NO scavenger PTIO significantly enhanced it, compared to vehicle controls. These data suggest that an overall effect of NO production in the trigeminal nucleus is pronociceptive, but NO extracellularly diffused out of its producing neurons would have an antinociceptive action.

• Molecules and Cells
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• 제27권4호
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• pp.417-422
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• 2009

Lipoxygenase (LO) metabolites are generated in inflamed tissues. However, it is unclear whether the inhibition of the LO activity regulates the expression of c-Fos protein, a pain marker in the spinal cord. Here we used a carrageenan-induced inflammation model to examine the role of LO in the development of c-Fos expression. Intradermally injected carrageenan caused elevated number of cells exhibiting Fos-like immunoreactivity (Fos-LI) in the spinal dorsal horn, and decreased the thermal and mechanical threshold in Hargreaves and von Frey tests. Pretreatment with an inhibitor of phospholipase A2, that generates the LO substrate, prior to the carrageenan injection significantly reduced the number of Fos-(+) cells. A general LO inhibitor NDGA, a 5-LO inhibitor AA-861 and a 12-LO inhibitor baicalein also exhibited the similar effects. Moreover, the LO inhibitors suppressed carrageenan-induced thermal and mechanical hyperalgesic behaviors, which inidcates that the changes in Fos expression correlates with those in the nociceptive behaviors in the inflamed rats. LO products are endogenous TRPV1 activators and pretreatment with BCTC, a TRPV1 antagonist inhibited the thermal but not the mechanical hypersensitivity. Overall, our results from the Fos-LI and behavior tests suggest that LO products released from inflamed tissues contribute to nociception during carrageenan-induced inflammation, indicating that the LO pathway is a possible target for modulating inflammatory pain.

• The Korean Journal of Physiology
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• 제24권2호
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• pp.389-402
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• 1990

The physiological characteristics of the neurons receiving the ventral root afferent inputs were investigated in the cat. A total of 70 cells were identified in the lumbosacral spinal cord. All these cells responded only to the C-strength stimulation of the distal stump of cut ventral root and the estimated conduction velocities of the VRA fibers were not faster than 4 m/sec. The majority of them were silent in resting state. For 49 cells, their peripheral receptive fields were characterized. Among them, 25 cells were exclusively excited by VRA inputs, 8 were inhibited and the remaining cells recevied both excitatory and inhibitory VRA inputs. According to the response pattern to the mechanical stimuli applied to their receptive fields, only a fourth of them were typical high threshold cell, a sixth, wide dynamic range cells, while remainings were a rather complex cells. Most of the cells receiving VRA inputs, received only the A ${\delta}-peripheral$ nerve inputs. Intravenous injection of morphine decreased the response of spinal cells to the VRA activation. The responses were abolished completely by counter irritation to the common peroneal nerve with C-strength-low frequency stimuli. These physiological properties of the spinal neurons receiving the VRA inputs are differ in some aspect from the spinal neurons receiving nociceptive inputs from the periphery, but still were consistent with the contention that VRA system might carry nociceptive informations arising from the spinal cord and/or neraby surrounding tissues.

• Journal of Korean Neurosurgical Society
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• 제43권2호
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• pp.97-104
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• 2008

Objective: Transient receptor potential vanilloid subfamily type 1 (TRPV1), a most specific marker of the nociceptive primary afferent, is expressed in peptidergic and non-peptidergic primary afferents innervating skin and viscera. However, its expression in sensory fibers to skeletal muscle is not well known. In this study, we studied the neurochemical characteristics of TRPV1-positive primary afferents to skeletal muscles. Methods: Sprague-Dawley rats were injected with total $20{\mu}l$ of 1% fast blue (FB) into the gastrocnemius and erector spinae muscle and animals were perfused 4 days after injection. FB-positive cells were traced in the L4-L5 (for gastrocnemius muscle) and L2-L4 (for erector spinae muscle) dorsal root ganglia. The neurochemical characteristics of the muscle afferents were studied with multiple immunofluorescence with TRPV1, calcitonin gene-related peptide (CGRP) and $P2X_3$. To identify spinal neurons responding to noxious stimulus to the skeletal muscle, 10% acetic acids were injected into the gastrocnemius and erector spinae muscles and expression of phospho extracellular signal-regulated kinase (pERK) in spinal cords were identified with immunohistochemical method. Results: TRPVl was expressed in about 49% of muscle afferents traced from gastrocnemius and 40% of erector spinae. Sixty-five to 60% of TRPV1-positive muscles afferents also expressed CGRP. In contrast, expression of $P2X_3$ immnoreaction in TRPV1-positive muscle afferents were about 20%. TRPV1-positive primary afferents were contacted with spinal neurons expressing pERK after injection of acetic acid into the muscles. Conclusion: It is consequently suggested that nociception from skeletal muscles are mediated by TRPV1-positive primary afferents and majority of them are also peptidergic.

• The Korean Journal of Physiology and Pharmacology
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• 제28권1호
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• pp.73-81
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• 2024

The substantia gelatinosa (SG) within the trigeminal subnucleus caudalis (Vc) is recognized as a pivotal site of integrating and modulating afferent fibers carrying orofacial nociceptive information. Although naringenin (4',5,7-thrihydroxyflavanone), a natural bioflavonoid, has been proven to possess various biological effects in the central nervous system (CNS), the activity of naringenin at the orofacial nociceptive site has not been reported yet. In this study, we explored the influence of naringenin on GABA response in SG neurons of Vc using whole-cell patch-clamp technique. The application of GABA in a bath induced two forms of GABA responses: slow and fast. Naringenin enhanced both amplitude and area under curve (AUC) of GABA-mediated responses in 57% (12/21) of tested neurons while decreasing both parameters in 33% (7/21) of neurons. The enhancing or suppressing effect of naringenin on GABA response have been observed, with enhancement occurring when the GABA response was slow, and suppression when it was fast. Furthermore, both the enhancement of slower GABA responses and the suppression of faster GABA responses by naringenin were concentration dependent. Interestingly, the nature of GABA response was also found to be sex-dependent. A majority of SG neurons from juvenile female mice exhibited slower GABA responses, whereas those from juvenile males predominantly displayed faster GABA responses. Taken together, this study indicates that naringenin plays a partial role in modulating orofacial nociception and may hold promise as a therapeutic target for treating orofacial pain, with effects that vary according to sex.

• The Korean Journal of Pain
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• 제22권1호
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• pp.16-20
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• 2009

Background: Zaprinast is an inhibitor of phosphodiesterase 5, 6 and 9. Phosphodiesterase inhibitors could produce anti-nociceptive effects by promoting the accumulation of cGMP. We hypothesized that intrathecal zaprinast could attenuate the allodynia induced by chronic constriction injury of the sciatic nerve in rat. Methods: Sprague-Dawley rats were prepared with four loose ligations of the left sciatic nerve just proximal to the trifurcation into the sural, peroneal and tibial nerve branches. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. The thresholds for the withdrawal responses were assessed. Zaprinast ($3-100{\mu}g$) was administered intrathecally by the direct lumbar puncture method to obtain the dose-response curve and the 50% effective dose ($ED_{50}$). Measurements were taken before and 15, 30, 45, 60, 90, 120, and 180 min after the intrathecal doses of zaprinast. The side effects were also observed. Results: Intrathecal zaprinast resulted in a dose-dependent antiallodynic effect. The maximal effects occurred within 15-30 min and then they gradually decreased down to the baseline level over time in all the groups. There was a dose dependent increase in the magnitude and duration of the effect. The $ED_{50}$ value was $17.4{\mu}g$ (95% confidence intervals; $14.7-20.5{\mu}g$). No severe motor weakness or sedation was observed in any of the rats. Conclusions: Intrathecally administered zaprinast produced a dose-dependent antiallodynic effect in the chronic constriction injury neuropathic pain model. These findings suggest that spinal phosphodiesterase 5, 6 and 9 may play an important role in the modulation of neuropathic pain.

• International Journal of Oral Biology
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• 제36권3호
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• pp.143-148
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• 2011

The present study investigated the role of peripheral P2X receptors in inflammatory pain transmission in the orofacial area in rats. Experiments were carried out on male Sprague-Dawley rats weighing 220 to 280 g. Formalin (5%, 50 ${\mu}L$) and complete Freund's adjuvant (CFA, 25 ${\mu}L$) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. TNP-ATP, a $P2X_{2,2/3,4}$ receptor antagonist, or OX-ATP, a $P2X_7$ receptor antagonist, was then injected subcutaneously at 20 minutes prior to formalin injection. One of the antagonists was administered subcutaneously at three days after CFA injection. The subcutaneous injection of formalin produced a biphasic nociceptive behavioral response. Subcutaneous pretreatment with TNP-ATP (80, 160 or 240 ${\mu}g$) significantly suppressed the number of scratches in the second phase produced by formalin injection. The subcutaneous injection of 50 ${\mu}g$ of OX-ATP also produced significant antinociceptive effects in the second phase. Subcutaneous injections of CFA produced increases in mechanical and thermal hypersensitivity. Both TNP-ATP (480 ${\mu}g$) and OX-ATP (100 ${\mu}g$) produced an attenuation of mechanical hypersensitivity. However, no change was observed in thermal hypersensitivity after the injection of either chemical. These results suggest that the blockade of peripheral P2X receptors is a potential therapeutic approach to the onset of inflammatory pain in the orofacial area.

• International Journal of Oral Biology
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• 제40권2호
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• pp.71-77
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• 2015

The activation of glial cells in the spinal cord has been contribute to the initiation and maintenance of pain facilitation induced by peripheral inflammation and nerve injury. The present study investigated effects of botulinum toxin type A (BoNT-A), injected subcutaneously or intracisternally, on the expression of microglia and astrocytes in rats. Complete Freund's Adjuvant (CFA)-induced inflammation was employed as an orofacial chronic inflammatory pain model. A subcutaneous injection of $40{\mu}L$ CFA into the vibrissa pad was performed under 3% isoflurane anesthesia in SD rats. Immunohistochemical analysis for changes in Iba1 (a microglia marker) and GFAP (an astrocyte marker), were performed 5 days after CFA injection. Subcutaneous injection of CFA produced increases in Iba1 and GFAP expression, in the ipsilateral superficial lamia I and II in the medullary dorsal horn of rats. Subcutaneous treatment with BoNT-A attenuated the up-regulation of Iba1 and GFAP expressions induced by CFA injection. Moreover, intracisternal injection of BoNT-A also attenuated the up-regulated Iba1 and GFAP expressions. These results suggest that the anti-nociceptive action of BoNT-A is mediated by modulation activation of glial cells, including microglia and astrocyte.

• Journal of Dental Anesthesia and Pain Medicine
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• 제21권3호
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• pp.183-205
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• 2021

This systematic review and meta-analysis aimed to analyze the effectiveness of maxillary stabilization splint (SS) therapy to reduce headache (HA) intensity and HA frequency in patients with temporomandibular disorders (TMD)-HA comorbidity. Randomized controlled trials (RCTs) using full-arch coverage, hard resin, and maxillary SS therapy were included. Electronic databases, including Cochrane Library, MEDLINE through PubMed, Web of Science, and EMBASE, were searched. The risk of bias was analyzed based on Cochrane's handbook. The search yielded 247 references up to January 28, 2020. Nine RCTs were included at a high risk of bias. The comparison groups included other splints, counseling, jaw exercises, medications, neurologic treatment, and occlusal equilibration. Four studies reported a statistically significant reduction in HA intensity, and five studies reported significant improvement in HA frequency from baseline at 2-12 months in patients with TMD-HA comorbidity treated with a full-arch hard maxillary SS. HA frequency in tension-type HA (TTH) comorbid with TMD diagnoses of myofascial pain (MFP) or capsulitis/synovitis improved significantly with SS than that with full-arch maxillary non-occluding splint (NOS) in two studies. Comparison groups receiving hard partial-arch maxillary splint nociceptive trigeminal inhibition (NTI) showed statistically significant improvements in HA intensity in patients with mixed TMD phenotypes of MFP and disc displacement comorbid with "general HA." Comparison groups receiving partial-arch maxillary resilient/soft splint (Relax) showed significant improvements in both HA intensity and frequency in patients with HA concomitant with MFP. The meta-analysis showed no statistically significant difference in the improvement of pain intensity at 2-3 months with comparison of the splints (partial-arch soft [Relax], hard [NTI], and full-arch NOS) or splint use compliance at 6-12 months with comparison of the splints (partial-arch Relax and full-arch NOS) versus the SS groups in patients with various TMD-HA comorbidities. In conclusion, although SS therapy showed a statistically significant decrease in HA intensity and HA frequency when reported, the evidence quality was low due to the high bias risk and small sample size. Therefore, further studies are required.

• 생명과학회지
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• 제20권4호
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• pp.496-502
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• 2010

산성 식염수 쥐모델은 사람의 섬유근통에 근접한 모델로 제시되고 있다. 포도씨에서 얻은 oligomeric proanthocyanidin complexes (OPC)는 항산화제로 알려져 있다. 저자들은 산성 식염수 모델에서 통증 역치에 대한 OPC의 효과를 연구했다. 좌측 장딴지 근육에 pH 4.0의 산성 식염수 $100\;{\mu}l$를 0일과 5일에 주사했다. 대조군은 pH 7.2의 생리 식염수를 같은 스케줄로 주사했다. 산성 식염수 그룹 10마리를 다시 두 그룹으로 나누어 한 그룹은 멸균 식염수, 다른 한 그룹은 OPC 300 mg/kg를 복강 내 주사했다. 복강 내 주사 한시간 후 다시 통각에 대한 역치를 조사했다. 0일에 비해 7일에서 산성 식염수 모델은 기계적 과통각을 나타냈다(p<0.05). OPC 300 mg/kg를 복강내 주사한 그룹에서 강력한 항통각 효과를 나타냈다(주사측 발바닥, p=0.001; 반대측 발바닥, p=0.002). 면역조직화학 염색상 복강내 식염수를 처치한 대조군에 비해 OPC 처치군에서 대뇌의 M1 및 M2 영역에서 산-감지 이온 통로3의 발현이 감소되었다(p<0.05). 사람의 섬유근통에서 OPC 치료의 효과를 보기 위한 연구가 향후 필요할 것으로 생각된다.