Inhibition of Fast Nerve Conduction Produced by Analgesics and Analgesic Adjuvants—Possible Involvement in Pain Alleviation

Abstract

Nociceptive information is transmitted from the periphery to the cerebral cortex mainly by action potential (AP) conduction in nerve fibers and chemical transmission at synapses. Although this nociceptive transmission is largely inhibited at synapses by analgesics and their adjuvants, it is possible that the antinociceptive drugs inhibit nerve AP conduction, contributing to their antinociceptive effects. Many of the drugs are reported to inhibit the nerve conduction of AP and voltage-gated Na+ and K+ channels involved in its production. Compound action potential (CAP) is a useful measure to know whether drugs act on nerve AP conduction. Clinically-used analgesics and analgesic adjuvants (opioids, non-steroidal anti-inflammatory drugs, α2-adrenoceptor agonists, antiepileptics, antidepressants and local anesthetics) were found to inhibit fast-conducting CAPs recorded from the frog sciatic nerve by using the air-gap method. Similar actions were produced by antinociceptive plant-derived chemicals. Their inhibitory actions depended on the concentrations and chemical structures of the drugs. This review article will mention the inhibitory actions of the antinociceptive compounds on CAPs in frog and mammalian peripheral (particularly, sciatic) nerves and on voltage-gated Na+ and K+ channels involved in AP production. Nerve AP conduction inhibition produced by analgesics and analgesic adjuvants is suggested to contribute to at least a part of their antinociceptive effects.

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review

“…Whether and to what extent the Nav blockade of these drugs is responsible for their analgesic effect observed in humans remain unclear. In vitro opioid studies examining morphine, tramadol, fentanyl, sufentanil, and buprenorphine showed a decrease in action potential amplitudes and conduction via direct action on Nav and Kv channels in frog sciatic nerves [ 138 ], and on unmyelinated mouse C-fibers [ 139 ]. Moreover, loperamide inhibited Nav1.7 and Nav1.8 as well in an in vitro study [ 140 ].…”

“…NSAIDs such as diclofenac, aceclofenac, indomethacin, tolfenamic, and flufenamic acid reduced action potential amplitudes and inhibited nerve conduction through Nav inhibition in frog sciatic nerves in a concentration-dependent manner, probably due to their chemical structure being similar to local anesthetics [ 138 ]. A similar inhibitory effect on the action potential was observed after application of clonidine (α2-AR agonist) on frog sciatic nerves, which was attributed to Nav blockade [ 138 ]. Moreover, ketamine was shown to directly inhibit Nav in neuroblastoma cells [ 141 ], which may account for the analgesic effect of ketamine as adjuvant to local anesthetic agents.…”

“…Topically administered NSAIDs may interfere with the nociceptive pathway by their ability to decrease the synthesis of proinflammatory PGs through inhibition of cyclooxygenase COX-2. Preclinical studies showed that locally administered diclofenac may also act on several ion channels (Nav, TRPV1, TRPA1, TRPM3, K + , NMDAR) at peripheral neurons, resulting in antinociception [ 138 , 169 , 226 , 228 , 229 ]. Peripheral antinociception induced by diclofenac may rely on release of noradrenaline and interaction with α1, α2C, and β-adrenoreceptors [ 230 ].…”

“…Opioids also inhibit adenylate cyclase, the enzyme converting ATP to cAMP [ 286 ]. Additionally, opioids such as morphine, tramadol, fentanyl, sufentanil, buprenorphine, and loperamide may influence Nav [ 138 , 139 , 140 ], inhibiting action potentials, which has been revealed in frog sciatic nerve models [ 138 ], and on unmyelinated mouse C-fibers [ 139 ].…”

Peripheral Mechanisms of Neuropathic Pain—The Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain

“…In clinical studies conducted in patients with PHN specific blocker of Nav1.7 (TV-45070) has been assessed as well, but no statistical difference was observed between active treatment and placebo for the change in mean daily pain scores from baseline compared with the last week [122] Other substances being suggested to exert their antinociceptive effect via Nav blockade in vitro in peripheral nerves include NSAIDs, opioids, α2-AR agonists, and plant-derived compounds, which has been extensively reviewed by Kumamoto [123].…”