Effects of mexiletine on algogenic mediator-induced nociceptive responses in mice.
To clarify the possible mechanism of the antinociceptive effect of mexiletine, the effects of the agent on formalin- and algogenic mediator-induced nociceptive responses were examined as compared to lidocaine. Subcutaneous (s.c.) injection of 0.5% formalin into the hindpaw caused an acute nociceptive response that lasted about 5 min (first phase). This response then disappeared completely for about 5 min and then recurred lasting about 20 min (second phase). Intraperitoneal (i.p.) administration of mexiletine (10 and 30 mg/kg) significantly and dose-dependently reduced the durations of the first and second phases of formalin-induced nociceptive response. On the other hand, although i.p. administration of lidocaine (10 and 30 mg/kg) had no significant effect on the first phase of formalin-induced nociceptive response, the duration of the second phase response was significantly and dose-dependently reduced. Pretreatment with mexiletine resulted in a significant and dose-dependent inhibition of the nociceptive response produced by intrathecal (i.t.) injection of substance P (0.1 nM), somatostatin (1.0 nM), bradykinin (1 microgram/mouse) and prostaglandin (PG) F2 alpha (1 microgram/mouse). Although lidocaine had no significant effect on the substance P- or somatostatin-induced nociceptive response, bradykinin- and PGF2 alpha-induced nociceptive responses were inhibited. These results suggest that the antinociceptive effect of mexiletine involves the inhibition of substance P-, somatostatin-, bradykinin- and PGF2 alpha-mediated nociceptive transmission in the spinal cord. Furthermore, it is possible that the weaker antinociceptive effect of lidocaine as compared with that of mexiletine may be due to the lack of its inhibitory effect on substance P- and somatostatin-mediated nociceptive transmission in the spinal cord.
Hitosugi
H
H
Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Kashiwazaki
T
T
Ohsawa
M
M
Kamei
J
J
D000700:Analgesics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000633:toxicity; D015232:Dinoprostone / Q000633:toxicity; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D013004:Somatostatin / Q000633:toxicity; D013373:Substance P / Q000633:toxicity
D000700:Analgesics; D000779:Anesthetics, Local; D008801:Mexiletine; D013373:Substance P; D013004:Somatostatin; D008012:Lidocaine; D015232:Dinoprostone; D001920:Bradykinin