Analgesic effects of intra-nasal enkephalins.
The analgesic effects of intranasal delivery of leucine enkephalin (Leu-Enk) and its synthetic analogue [D-ala(2)]-leucine enkephalinamide (YAGFL) with or without enzyme inhibitors and/or absorption enhancers were investigated using the acetic acid-induced writhing test in mice. The analgesic activity was significantly affected by the time delay after the administration of Leu-Enk; the inhibition rates for the groups administered with acetic acid 5 min and 30 min after the administration of Leu-Enk were 56.40 +/- 8.54 and 17.98 +/- 7.07%, respectively. The addition of enzyme inhibitors and absorption enhancers markedly increased the inhibition rate of Leu-Enk and YAGFL; their inhibition rates were about four times and twice those without any enzyme inhibitor or absorption enhancer, respectively. The enzyme inhibitors and absorption enhancers that produced the highest inhibition rates of Leu-Enk and YAGFL were azelaic acid (1%), thimerosal (0.5 mM, TM), ethylenediamine-tetraacetic acid (5 mM, EDTA) and L-alpha-lysophosphatidylcholine (0.5%, LPC), and TM (0.5 mM), EDTA (5 mM), LPC (0.5%) and povidone (5%), respectively. The ED50 value of both enkephalins was also determined and found to be about 13 microg kg(-1), which is 850 and 60 times more potent than literature values for ketoprofen and morphine, respectively. Based on these results it was concluded that Leu-Enk or YAGFL could exert very high analgesic activity when administered nasally with a combination of inhibitors and absorption enhancers as compared with other analgesics.
Gwak
H S
HS
Laboratory of Clinical Pharmacy, College of Pharmacy, Chosun University, South Korea.
Cho
Y M
YM
Chun
I K
IK
D019342:Acetic Acid / Q000008:administration & dosage / Q000633:toxicity; D000281:Administration, Intranasal; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004357:Drug Synergism; D004492:Edetic Acid / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007660:Ketoprofen / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D013501:Surface-Active Agents / Q000494:pharmacology; D013849:Thimerosal / Q000494:pharmacology
D000700:Analgesics; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D013501:Surface-Active Agents; D013849:Thimerosal; D004743:Enkephalin, Leucine; C048614:enkephalinamide-Leu; D007660:Ketoprofen; D004492:Edetic Acid; C010038:azelaic acid; D019342:Acetic Acid