Two mechanisms for the meperidine block of action potential production in frog's skeletal muscle; non‐specific and opiate drug receptor mediated blockade.

Abstract

SUMMARYThe effects of meperidine and naloxone, and their interaction effects on action potential production in frog's sartorius muscle fibres, were studied with intracellular micro-electrode techniques.1. Meperidine, a narcotic analgesic drug, depressed the rate of rise, the rate of fall and the amplitude of the action potentials.2. At a meperidine concentration of 0 35 mm, the depression in the action potential maximum rate of rise followed a diphasic time course. At first there was a rapid reduction in the maximum rate of rise which was levelling off at about 60 % of control 60-90 min after drug application.This was followed by the second phase during which there was an initial rapid decrease in the maximum rate of rise and all surface fibres were inexcitable by 180 min.3. The addition of naloxone, a narcotic antagonist, in low concentrations (3 x 10-5 to 3 x 10-4 mM) at 70-90 min blocked the second phase of the meperidine-induced depression.4. With lower concentrations of meperidine (0.18 and 0'07 mM) the depression usually developed more slowly (up to 6 hr with the latter dose) and the addition of low naloxone concentrations partially antagonized the effects of meperidine. However, under no conditions was it possible to completely antagonize the effects of meperidine by the addition of naloxone.5. A linear relation was found between action potential amplitude and the action potential maximum rate of fall.6. Meperidine caused a shift in the relation of rate of fall against amplitude to higher action potential amplitudes, indicating that the drug inhibited the increase in potassium conductivity (g9) associated with the falling phase of the action potential. GEORGE B. FRANK 7. When low naloxone concentrations antagonized the effects of meperidine on the rate of rise and restored action potential amplitudes to control levels, the effect of meperidine on the maximum rate of fall was not antagonized.8. Larger naloxone concentrations (1.5 x 10-2 mM or more) depressed the action potential rate of rise but did not alter the relation between action potential amplitude and the maximum rate of fall.9. It is proposed that meperidine blocks action potential production by two mechanisms: (i) a non-specific mechanism in which the increases in both 9Na and qE are depressed and (ii) an opiate drug receptor mediated mechanism causing a specific depression of YNa.10. The impression gained from the results is that there are opiate drug receptors located on the inner surface of the muscle membrane associated with the 'sodium channels' and that drug activation of these receptors by either meperidine or high naloxone concentrations interferes with the opening of the 'sodium channels' normally produced by membrane depolarization.

Opioid effects of racemic ketamine on the excitability of sciatic nerve and skeletal muscle fibers of the frog.

“…The large decrease in the maximum rate of fall of the intracellularly recorded skeletal muscle action potential produced by ketamine (Fig. 4) also is consistent with a local anesthetic effect (19). Thus we would conclude that part of the depression produced by ketamine is due to a local anesthetic effect.…”

“…2). Again this is similar to the non-peptide opioid drugs which were shown to block excitability at higher concentrations by a local anesthetic-like effect (17,19,22). The mechanism(s) for the non-opioid depressant effects of ketamine were not investigated in this study.…”

“…In most instances, the muscle fibers were stimulated initially with supramaximal 0.5 msec pulses delivered through a stimulus isolator unit (WP Instru ments, model 305). Most of the techniques employed have been described in detail in previous papers (19,24).…”

“…However, in the only study which tested for this possible effect (13), both drugs were used in high con centrations; i.e., 1-2x10-3 M ketamine and 1-2.5x10-5 M naloxone. Since high con centrations of many drugs, including opioids, produce nonspecific local anesthetic-like ef fects (18,19) and high naloxone concentra tions tend to have opiod agonist (17,19,20,21), it is not surprising that Artem and Rydqvist observed only additive effects. In the present study when tested using lower concentrations of both drugs, naloxone was found to partially antagonize the depression of the action potential produced by ketamine in frog's sciatic nerve axons and skeletal muscle fibers.…”

The Effects of Morphine and Morphine-Related Compounds on the Rate of Afferent Discharges from the Pulmonary Receptors in Bullfrog

“…The chemoreceptors were powerfully inhibited by methionine-enkephalin, and the inhibitory effects of morphine were antagonized by naloxone (14). Frank (2) reported that naloxone in a low concentration (3x10-5 to 3X10-4 mM) acted as a narcotic antagonist, and in a high concentration (1.5X10-2 MM or more), it exerted an action almost identical to that of narcotics on the ion conductance of the frog skeletal muscle membrane.…”