Analgesic effects of JCM-16021 on neonatal maternal separation-induced visceral pain in rats.
OBJECTIVE
To investigate the pharmacological effect of JCM-16021, a Chinese herbal formula, and its underlying mechanisms.


METHODS
JCM-16021 is composed of seven herbal plant materials. All raw materials of the formula were examined according to the quality control criteria listed in the Chinese Pharmacopeia (2005). In a neonatal maternal separation (NMS) model, male Sprague-Dawley rats were submitted to daily maternal separation from postnatal day 2 to day 14, or no specific handling (NH). Starting from postnatal day 60, rats were administered JCM-16021 (2, 4, 8 g/kg per day) orally twice a day for 28 d. Pain threshold pressure and electromyographic activities of external oblique muscles in response to colorectal distention recorded with a Power Lab System (AD Instruments International), were tested as pain indices. Changes in serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the colon of rats were analyzed; the enterochromaffin cell numbers and serotonin transporter in the colon of rats were also evaluated with an immunohistochemistry method.


RESULTS
NMS treatment significantly reduced pain threshold pressure (37.4 +/- 1.4 mmHg), as compared to that of NH rats (57.7 +/- 1.9 mmHg, P < 0.05). After JCM-16021 treatment, the pain threshold pressure significantly increased when compared to that before treatment (34.2 +/- 0.9 mmHg vs 52.8 +/- 2.3 mmHg in the high dose group, 40.2 +/- 1.6 mmHg vs 46.5 +/- 1.3 mmHg in the middle dose group, and 39.3 +/- 0.7 mmHg vs 46.5 +/- 1.6 mmHg in the low dose group, P < 0.05). Also JCM-16021 significantly and dose-dependently decreased electromyographic activity to the graded colorectal distension (CRD), (the mean DeltaAUC values were: 0.17 +/- 0.03, 0.53 +/- 0.15, 1.06 +/- 0.18, 1.22 +/- 0.24 in the high dose group; 0.23 +/- 0.04, 0.68 +/- 0.17, 1.27 +/- 0.26, 1.8 +/- 0.3 in the middle dose group; and 0.29 +/- 0.06, 0.8 +/- 0.16, 1.53 +/- 0.24, 2.1 +/- 0.21 in the low dose group for the pressures 20, 40, 60, 80 mmHg), as compared to the NMS vehicle group. The mean DeltaAUC values were: 0.57 +/- 0.12, 1.33 +/- 0.18, 2.57 +/- 0.37, 3.08 +/- 0.37 for the pressures 20, 40, 60, 80 mmHg (P < 0.05). JCM-16021 treatment significantly reduced the 5-HT concentrations (from high, middle and low dosage groups: 60.25 +/- 5.98 ng/100 mg, 60.32 +/- 4.22 ng/100 mg, 73.31 +/- 7.65 ng/100 mg), as compared to the NMS vehicle groups (93.11 +/- 9.85 ng/100 mg, P < 0.05); and increased the 5-HIAA concentrations (after treatment, from high, middle and low dosage groups: 54.24 +/- 3.27 ng/100 mg, 50.34 +/- 1.26 ng/100 mg, 51.37 +/- 2.13 ng/100 mg) when compared to that in the NMS vehicle group (51.75 +/- 1.98 ng/100 mg, P < 0.05); but did not change the enterochromaffin cell numbers in the colon of rats. In addition, NMS rats had higher SERT expression (n = 10) than NH rats (n = 8, P < 0.05). JCM-16021 treatment significantly decreased SERT expression when compared to the NMS group (P < 0.01-0.001).


CONCLUSIONS
JCM-16021 can attenuate visceral hypersensitivity, and this analgesic effect may be mediated through the serotonin signaling pathway in the colon of rats.
Bian
Zhao-Xiang
ZX
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. bzxiang@hkbu.edu.hk
Zhang
Man
M
Han
Quan-Bin
QB
Xu
Hong-Xi
HX
Sung
Joseph J Y
JJ
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001010:Anxiety, Separation / Q000150:complications* / Q000523:psychology; D003106:Colon / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D004576:Electromyography; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008426:Maternal Deprivation; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D000700:Analgesics; D004365:Drugs, Chinese Herbal; C549084:JCM-16021; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid