Analgesics and analgesic adjuvants inhibiting nerve conduction in the frog sciatic nerve —local anesthetics, opioids, α2 adrenoceptor agonists, antiepileptics, antidepressants and NSAIDs

Abstract

Many of analgesics and analgesic adjuvants act on nerve conduction and synaptic transmission in the nervous system to inhibit nociceptive transmission. It has not been fully examined how nerve conduction inhibition leading to antinociception differs in extent among various analgesics and analgesic adjuvants. We examined quantitatively their actions on fast–conducting compound action potentials (CAPs) recorded from the frog sciatic nerve. Drugs tested were local anesthetics, opioids, adrenoceptor agonists, antiepileptics, antidepressants and non–steroidal anti– inflam matory drugs (NSAIDs). As a result, we found that many of their drugs reduce the peak amplitude of the CAPs in a manner dependent on their chemical structures. Consistent with voltage–gated Na + –channel inhibition produced by local anesthetics, CAP peak amplitudes were reduced by procaine, cocaine, tetracaine, prilocaine, lidocaine, ropivacaine, levobupivacaine and pramoxine with the half– maximal inhibitory concentration (IC 50 ) values of 2 . 2 , 0 . 80 , 0 . 013 , 1 . 8 , 0 . 74 , 0 . 34 , 0 . 23 and 0 . 21 mM, respectively. A weak opioid tramadol reduced CAP peak amplitude s (IC 50 = 2 . 3 mM) more effectively than its metabolite mono– O – demethyl–tramadol; this distinction was attributed to such a difference in chemical structure that tramadol and mono– O –demethyl–tramadol have –OCH 3 and –OH bound to a benzene ring, respectively. Moreover, NSAIDs [tolfenamic acid, meclofenamic acid and flufenamic acid (IC 50 values: 0 . 29 , 0 . 19 and 0 . 22 mM, respectively)]. On the other hand, salicylic acid–based (aspirin), propionic acid–based (ketoprofen, ibuprofen, naproxen, loxoprofen and flurbiprofen) and enolic acid–based (meloxicam and piroxicam) NSAIDs had no effect on CAPs. In conclusion, CAP inhibitions produced by local anesthetics were partly comparable in extent to those of a 2 –adrenoceptor agonists, antiepileptics, antidepressants and NSAIDs; opioids inhibited CAPs less potently than their drugs. It is suggested that analgesics and analgesic adjuvants inhibit nerve conduction in a manner dependent on their chemical structures.