Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model.
Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic agents, including the vinca alkaloids such as vincristine. The resulting symptoms, which frequently include moderate to severe pain, can often be disabling. The current study utilized a vincristine-induced neuropathic pain animal model [Pain 93 (2001) 69], in which rats were surgically implanted with mini-osmotic pumps set to deliver vincristine sulfate (30 microg kg(-1)day(-1), i.v.), to examine the time course of progression of various pain modalities and to compare the dose-response effects of clinically utilized drugs on mechanical allodynia to further validate the relevance of this model to clinical pathology. Vincristine infusion resulted in significant cold allodynia after 1 week post-infusion, however mechanical and thermal nociception showed little to no effect. In contrast, marked mechanical allodynia occurred by 1 week of vincristine infusion and returned nearly to pre-infusion levels by the 4th week after infusion pump implantation. ED(50) values (micromol/kg, p.o.) were determined in the mechanical allodynia assay for lamotrigine (82), dextromethorphan (94), gabapentin (400), acetaminophen (1100) and carbamazepine (3600); however, aspirin and ibuprofen had no effects up to 300 and 1000 micromol/kg, respectively. Additionally, ED(50) values (micromol/kg, i.p.) were determined in the mechanical allodynia assay for clonidine (0.35) and morphine (0.62), but desipramine and celecoxib had no effects up to 66 and 260 micromol/kg, respectively. Findings from the current, preclinical study further validate this model as clinically relevant for chemotherapy-induced pain. The surprisingly good effects observed with acetaminophen warrant further investigation of its mechanism(s) of action in neuropathic pain.
Lynch
James J
JJ
Neuroscience Research, Global Pharmaceutical Research and Development, Dept. R4N5, Abbott Laboratories, Bldg. AP9A-LL, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA.
Wade
Carrie L
CL
Zhong
Chengmin M
CM
Mikusa
Joseph P
JP
Honore
Prisca
P
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006941:Hyperesthesia / Q000188:drug therapy* / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014750:Vincristine
D000700:Analgesics; D014750:Vincristine