Profiling the Effects of Repetitive Morphine Administration on Motor Behavior in Rats.

Alok K Paul,Nuri Gueven,Nikolas Dietis

doi:10.3390/molecules26144355

Alok K Paul, Nuri Gueven + Show 1 more

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https://doi.org/10.3390/molecules26144355

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Abstract

Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereas analgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levels of analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing on non-analgesic effects has been overlooked. This study aimed to characterize morphine-induced behavior and the development and progression of morphine-induced behavioral tolerance. Adult male Sprague–Dawley rats were repetitively treated with subcutaneous morphine for 14 days in two dose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day). Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in an open-field arena, before and 30 min post-injections. Antinociception was measured using tail-flick and hot-plate assays. All measured parameters were highly suppressed in both dosing groups on the first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatment progressed. Animals in the high-dose group showed increased locomotor activity after 10 days of morphine treatment. This excitatory phase converted to an inhibition of behavior when a higher morphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive high-dose morphine exposure represent a signature of its behavioral and antinociceptive tolerance.

Highlights

Long-term clinical use of opioids such as morphine is limited by its significant side effects such as drowsiness, itching, respiratory depression, constipation, addiction, and dependence [1,2,3]
Pain.NevertheNevertheless, long-term use of morphine is severely limited by its biphasic effects on motor behavior less, long-term use of morphine is severely limited by its biphasic effects on motor behav(inhibitory or excitatory) and the manifestation of analgesic tolerance
Despite increased knowledge of the different activities of morphine, known about how dosing regimens affect the manifestation of motor behavioral effects

Summary

Introduction

Long-term clinical use of opioids such as morphine is limited by its significant side effects such as drowsiness, itching, respiratory depression, constipation, addiction, and dependence [1,2,3]. Predicting the appearance of morphine-induced side effects is important for effective pain relief, the relationship between opioid dosing and the appearance of drug-induced side effects is currently not well established. Pain relief and side effects appear to correlate poorly [4]. Behavioral side effects of morphine in different clinical studies are described as dose-dependent, such as pruritus [5], and dose-independent, such as nausea and vomiting [6,7]. It is important to understand how the dosing regimen can affect behavioral effects. Antinociceptive tolerance largely depends on morphine dose and dosing protocol, and a high starting dose or a high follow-up dose of morphine produces less antinociceptive tolerance [8]

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