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.
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. bzxiang@hkbu.edu.hk
Zhao-Xiang
ZX
Bian
Man
M
Zhang
Quan-Bin
QB
Han
Hong-Xi
HX
Xu
Joseph J Y
JJ
Sung
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