Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence.
ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.
Meng
Ge
G
Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
Wu
Ning
N
Zhang
Cheng
C
Su
Rui-Bin
RB
Lu
Xin-Qiang
XQ
Liu
Yin
Y
Yun
Liu-Hong
LH
Zheng
Jian-Quan
JQ
Li
Jin
J
D019342:Acetic Acid; D000700:Analgesics; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004361:Drug Tolerance; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy* / Q000523:psychology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000150:complications; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000188:drug therapy
D000700:Analgesics; D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; C531033:N-(1-(2,3-dimethoxyphenyl)-4-methyl-3-penten-1-yl)-1-(5-bromofurfuryl)-1-piperidyl-4-amine; D009292:Narcotic Antagonists; D010880:Piperidines; D009270:Naloxone; D009020:Morphine; D019342:Acetic Acid