• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1994.04a
• /
• pp.287-287
• /
• 1994

In the present study, it was aimed to asses the possibility that calcitonin gene-related peptide (CGRP) released in response to transient hypotension may contribute to the reflex autoregulation of cerebral blood flow as a putative modulator. Changes in pial arterial diameter (mean, 33.0 ${\pm}$ 1.1 $\mu\textrm{m}$) with changes in systemic arterial blood pressure (mean, 101.9 ${\pm}$ 2.7 mmHg) were observed directly through a closed cranial window in anesthetized normotensive rats. Image of the pial vessels was captured with a stereoscope connected to a CCD video camera and the diameter was measured with a microscaler. In the capsaicin-treated rats (one day prior to experiment, 50 nmol capsaicin injected intracisternally), both vasodilater and vasoconstrictor responses evoked by a transient hypotension and the reverse of blood pressure were markedly attenuated or almost abolished. When changes in pial arterial diameter were plotted as a function of changes in blood pressure, the slopes of both regression lines (for vasodilators and vasoconstrictors ) were markedly reduced. Similar reductions were evidenced under treatment wi th the CGRP antibody serum (1:1,000) and following CGRP receptor desensitization. However, the autoregulatory mechanics were neither affected by treatment wi th spantide (1 ${\mu}$M), substance P antagonist, nor by substance P receptor desensitization. Suffusion wi th mock cerebrospinal fluid containing CGRP and cromakalim caused a vasodilatation in a concentration-dependent manner, respectively and their effects were antagonized by glibenclamide. Substance P produced a vasodilatation, which was, however, little affected by glibenclamide. These observations indicate that the CGRP released from the perivascular sensory fibers in response to a hypotension is implicated in the modulation of the autoregulation of cerebral blood flow.

• Restorative Dentistry and Endodontics
• /
• v.45 no.3
• /
• pp.40.1-40.12
• /
• 2020

Objectives: The aim of this study was to evaluate the effects of endodontic treatment on levels of substance P (SP) and calcitonin gene-related peptide (CGRP) in the saliva of patients with symptomatic apical periodontitis. Materials and Methods: Twelve patients with mandibular molars with symptomatic apical periodontitis were enrolled in this study. An initial saliva sample was collected just before administration of anesthesia for root canal treatment, which was performed at the first visit. A second saliva sample was collected at a control visit 1 week after treatment. Salivary SP and CGRP levels were evaluated quantitatively using biochemical assays. The data were analyzed using Pearson correlation analysis, the paired samples t-test, and the Mann-Whitney U test (p = 0.05). Results: The postoperative salivary level of SP was significantly lower than the preoperative level (p = 0.005). However, the postoperative salivary level of CGRP was similar to the preoperative level (p = 0.932). Visual analog scale (VAS) scores of patients' subjective pain were found to be positively correlated with salivary levels of SP (r = 0.421; p = 0.040). No statistically significant correlations were observed between salivary levels of CGRP and VAS scores for patients' subjective percussion tenderness (p = 0.533) or VAS scores for patients' subjective pain (p = 0.459). Conclusions: According to the results of the present study, salivary SP levels may be used as an objective indicator in the diagnosis and assessment of the degree of pain in endodontic diseases.

• Restorative Dentistry and Endodontics
• /
• v.20 no.2
• /
• pp.527-537
• /
• 1995

The effect of calcitonin gene-related peptide (CGRP), substance P (SP) and electrical stimulation of the tooth on the intradental nerve activtiy (INA) was investigated in anesthetized cats. The INA was recorded from single pulp nerve units dissected from the inferior alveolar nerve under stereomicroscope. The INA elicited by 3 minute application of 4M NaCl in deep dentinal cavity was compared before and after stimulation at 10 minute intervals. The magnitude of INA was calculated as the total number of nerve impulses produced in given period, and the changes of INA are expressed as % of control INA. The results obtained were as follows. 1. 16 single pulp nerve units were classified as 14 $A{\delta}$-fibers (3.4~19.4m/sec) and 2-fibers (1.5~1.7m/sec) according to the conduction velocity. 2. 4M NaCl evoked an irregular bursts of spikes which continued until washing out. Isotonic saline did not affect INA to subsequent applications of the hypertonic NaCl solution (P>0.05). 3. Local application of CGRP ($200{\mu}g$/ml) in deep dentinal cavity reduced the INA induced by 4M NaCl in $A{\delta}$-fiber units (P<0.01) and some units of those responded to CGRP during application. 4. Local application of SP ($100{\mu}g$/ml) in deep dentinal cavity reduced the INA induced by 4M NaCl in AS-fiber units (p<0.05), but increased the INA in C-fiber unit coincided with large reduction of the INA of $A{\delta}$-fiber units. 5. Monopolar electrical stimulation applied to the crown at intensities high enough to excite C-fibers (12V, 5ms, 10Hz, 10~30min) decreased the INA in $A{\delta}$-fiber units (P<0.01) and systemic pretreatment with phenoxybenzamine (3mg/kg, i.v.) enhanced this inhibitory effect (P<0.01). On the contrary, electrical stimulation increased the INA in C-fiber unit.

• Journal of Oral Medicine and Pain
• /
• v.34 no.4
• /
• pp.387-395
• /
• 2009

Nerve growth factor (NGF) and sensory neuropeptides are involved in the process of nociception at peripheral nerve fibers and wide spread in central nervous system. The aims of this study were to investigate NGF and sensory neuropeptides (substance P [SP] and calcitonin gene-related peptide [CGRP]) levels in human plasma and saliva, and the associations between these sensory neuropeptides levels and chronic orofacial pain symptoms. NGF, SP, and CGRP levels in plasma and resting whole saliva samples collected from 67 orofacial pain patients (joint pain, dental or periodontal pain, mucosal pain) and 36 pain free control subjects were measured by enzyme immunoassay. The characteristic pain intensity of each subject was measured using the Graded Chronic Pain Scale and the flow rate of resting whole saliva was measured. Joint pain patients group showed significantly higher plasma NGF level compared to each of dental pain patients (p<0.01), mucosal pain patients (p<0.01), and control group (p<0.01). Plasma NGF level of dental pain patients group was significantly higher than that of control group (p<0.01). Saliva SP level of dental pain patients group (p<0.05) and saliva CGRP level of mucosal pain group (p<0.05) were significantly higher than that of control group. Plasma and saliva SP levels of joint pain patients was significantly associated with pain intensity (plasma: standardized coefficient=0.599, p<0.01, saliva: standardized coefficient=0.504, p=0.05). In dental pain patients group, plasma SP (standardized coefficient=0.559, p<0.01), saliva SP (standardized coefficient=0.520, p<0.01) and saliva CGRP (standardized coefficient=0.599, p<0.01) levels were significantly associated with age. In mucosal pain patients group, plasma SP (standardized coefficient=0.495, p<0.05), saliva SP (standardized coefficient=0.500, p<0.05), and saliva CGRP (standardized coefficient=0.717, p<0.01) levels were significantly associated with age. NGF and neuropeptides may play a role in the maintenance of various orofacial pain symptoms. The examination of those levels in plasma and saliva helps understanding the mechanism of orofacial pain, and furthermore, can be applied to the diagnosis and therapy of orofacial pain.

• Restorative Dentistry and Endodontics
• /
• v.31 no.3
• /
• pp.153-160
• /
• 2006

We investigated the secretion of Interleukin-8 (IL-8) from ginviva and periodontal ligament stimulated with Substance P (SP) and Calcitonin Gene-related Peptide (CGRP). Gingiva (GF), periodontal ligament (PDLF) and pu)p (PF) tissues were collected from extracted intact 3rd molars. Cultured cells were stimulated with different concentrations of SP for 4 hrs, and stimulated with SP, CGRP and Tumor Necrosis Factor-$\alpha$ (TNF-$\alpha$) for 8 hrs. Then RNase Protection Assay was carried out. ELISA was performed using supernatants of stimulated cells for quantitative analysis of IL-8. Results were assessed using student t-test with significance of P<0.05. According to this study, the results were as follows: 1. IL-8 mRNA was detected in all type of cells studied (PF, GF and PDLF) 2. IL-8 mRNA expression was not increased after stimulating 4 hrs with SP ($10^{-5}M$) and SP ($10^{-8}M$) compared with Mock stimulation in all type of cells studied. 3. IL-8 mRNA expression was not increased after stimulating 8 hrs with SP ($10^{-4}M$) and CGRP ($10^{-6}M$) compared with Mock stimulation in all type or cells studied. 4. TNF-$\alpha$ (2 ng/ml) increased the expression of IL-8 mRNA in all kind of cells studied. 5. The secretion of IL-8 from GF was increased 8 hrs after the stimulation with CGRP ($10^{-6}M$)(p<0.05). 6. The secretion of IL-8 from PDLF was. increased 8 hrs after the stimulation with SP ($10^{-4}M$)(p<0.05). Calcitonin Gene-related Peptide (CGRP) increased Interleukin-8 (IL-8) which plays an important role in chemotaxis of neutrophil in Calcitonin Gene-related Peptide (CGRP) gingival tissue , whereas Substance P increased the secretion of IL-8 from periodontal ligament.

• Journal of Korean Neurosurgical Society
• /
• v.59 no.2
• /
• pp.98-105
• /
• 2016

Objective : Lumbar disc herniation can induce sciatica by mechanical compression and/or chemical irritation. The aim of this study was to compare the effects of GCSB-5 (Shinbaro$^{(R)}$) and NSAIDs on pain-related behavior and on the expressions of microglia, astrocytes, CGRP, TRPV1, IL-6, and CX3CL1 in a rat model of lumbar disc herniation. Methods : 112 male Sprague-Dawley rats underwent implantation of nucleus pulposus to a dorsal root ganglion (DRG). Rats were divided into five groups as follows; a saline group (the vehicle control group) (n=27), a 10 mg/kg aceclofenac group (the aceclofenac group) (n=22), and 100, 300 or 600 mg/kg GCSB-5 groups (the GCSB-5 100, 300, or 600 groups) (n=21 for each group). Rats were tested for mechanical allodynia at 3 days after surgery and at 1 day, 3 days, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, and 56 days after treatment commencement. Immunohistochemical staining of microglia (Iba1), astrocytes (GFAP), CGRP, and TRPV1, and PCR for IL-6 and CX3CL1 were performed on spinal dorsal horns and DRGs at 56 days after medication commencement. Results : After 56 days of GCSB-5 300 administration, mechanical withdrawal thresholds were significantly increased (p<0.05), and immunohistochemical expressions of Iba1, GFAP, CGRP, and TRPV1 were reduced than other groups, but this difference was not statistically significant. Conclusion : These results indicate GCSB-5 reduces mechanical allodynia and downregulates neuroglial activity and the expressions of CGRP and TRPV1 in the spinal segments of a rat model of lumbar disc herniation.

• The Korean Journal of Pain
• /
• v.19 no.2
• /
• pp.168-174
• /
• 2006

Background: Several biochemical mediators, such as substance P, calcitonin gene-related peptide (CGRP) and prostaglandin $E_2$, have been demonstrated to be involved in herniated or degenerated disc-induced radiculopathy. The authors tested the hypothesis that these mediators would existed in the epidural space of humans. Methods: Thirty nine patients were divided into two groups; 27 patients, who were diagnosed with spinal stenosis (stenosis group), and 12 scheduled for epidural anesthesia, without a history of back pain (control group). Under fluoroscopic guidance, an epidural catheter was introduced through the caudal space and placed into the anterior and posterior spaces, up to and around the epidural adhesive area, in the stenosis group. In the control group, the catheter was placed into the posterior epidural space through the L3⁣-4 or L4⁣-5 intervertebral space. Epidural irrigation was performed with 10 ml of saline, via an epidural catheter. Aspirated lavage fluid was collected, and the concentrations of biochemical mediators (substance P, CGRP and prostaglandin $E_2$) measured using an enzyme immunoassay kit. Results: Substance P, CGRP and prostaglandin $E_2$ were detected in all the epidural lavage fluids from both groups. The concentrations of substance P and prostaglandin $E_2$ in the stenosis group were higher than those of the control (P < 0.05). However, there was no difference in the CGRP levels between the two groups. In the stenosis group, the concentrations of these three mediators in the anterior epidural space were no different to those in the posterior space. Conclusions: These results suggest that biochemical mediators, such as substance P and prostaglandin $E_2$, in the epidural space might be partly involved in pain mechanism associated with spinal stenosis.

• The Korean Journal of Pain
• /
• v.35 no.2
• /
• pp.173-182
• /
• 2022

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

• Korean Journal of Veterinary Research
• /
• v.34 no.4
• /
• pp.727-734
• /
• 1994

To elucidate the effect of calcitonin gene-related peptide(CGRP), vasoactive intestinal peptide(VIP) and substance P was investigated with perivascular nerve stimulation and treatment of peptides from polygraph in the isolated renal artery of rabbit. 1. The neurogenic contraction induced by perivascular nerve stimulation was the frequency-dependent manner(264 Hz) in the isolated renal artery of rabbit. 2. CGRP and VIP caused the relaxation on the precontraction with noradrenaline($10{\mu}m$) on the presence and absence of endothelium in the isolated renal artery of rabbit. 3. Substance P caused the endothelium-dependent relaxation on the precontraction with noradrenaline($10{\mu}m$) in the isolated renal artery of rabbit. 4. CGRP and VIP inhibited the neurogenic contraction by the perivascular nerve stimulation(0.3 ms, 80 V, 50 Hz, 1 sec) on the absence and presence of endothelium in the isolated renal artery of rabbit. 5. Substance P inhibited on the neurogenic contraction by the perivascular nerve stimulation with the endothelium-dependent in the isolated renal artery of rabbit.

• Biomedical Science Letters
• /
• v.11 no.3
• /
• pp.375-382
• /
• 2005

This study aimed to investigate whether nociceptin is implicated in the, trigeminovascular responses to electrical stimulation of trigeminal ganglion in rats. An open cranial window was prepared on the right parietal bone of male Sprague-Dawley rats. Trigeminovascular system was stimulated by electrical stimulation of trigeminal ganglion (ETS; 5ms, 5Hz, 3V). Neonatal capsaicin treatment was performed with subcutaneous administration of capsaicin (50mg/kg) within the first 24 hours after birth. Changes in regional cerebral blood flow were continuously measured through the cranial window by laser-Doppler flowmetry, and the expression of nociceptin-like immunoreactivity was determined by immunohistochemistry. ETS caused increases in regional blood flow of pial arteriole in a voltage-dependent manner. ETS markedly and voltage-dependently increased the expression of nociceptin-like immunoreactivity in dura mater ipsilateral rather than contralateral to ETS. The nociceptin-like immunoreactivity was markedly reduced by pretreatments with calcitonin gene-related peptide(8-37) ($CGRP_{8-37},\;a\;CGRP_1$ receptor antagonist), L-733060 (a $NK_1$ receptor antagonist), and $[Nphe^1]$ nociceptin(1-13)$NH_2$ (a selective and competitive nociceptin receptor antagonist) as well as by neonatal capsaicin treatment. These results suggest that the electrical stimulation of trigeminal ganglion causes prominent expression of nociceptin within dura mater, in which not only neuropeptides inducing substance P and CGRP but also nociceptin are implicated in the trigeminovascular responses to electrical trigeminal ganglion stimulation.