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. 2022 Dec 22:15:4047-4054.
doi: 10.2147/JPR.S389929. eCollection 2022.

Long-Term Exposure to Morphine Induces Cross-Tolerance to Acute Antinociceptive Effect of Remifentanil on Somatic and Visceral Stimuli in Rats

Hideaki Mori  1 , Tatsuya Hashimoto  1 , Tetsuro Nikai  1 , Motohide Furuya  2 , Mai Hattori  1 , Yukiko Katsube  1 , Yoji Saito  1
Affiliations

Long-Term Exposure to Morphine Induces Cross-Tolerance to Acute Antinociceptive Effect of Remifentanil on Somatic and Visceral Stimuli in Rats

Hideaki Mori et al. J Pain Res. .

Abstract

Purpose: Remifentanil is one of the most commonly used opioids intraoperatively. Previous reports indicate that long-term use of opioids may lead to cross-tolerance to remifentanil, which poses a challenge in the control of acute pain intraoperatively. However, there is limited information regarding cross-tolerance to remifentanil, especially in visceral pain. Therefore, this study aimed to examine cross-tolerance to remifentanil in somatic and visceral tolerance using morphine-tolerant rats.

Methods: Six male Sprague-Dawley rats were allocated to the morphine and saline groups each. Tolerance to the antinociceptive effect of morphine was induced in rats in the morphine group. Remifentanil was continuously infused intravenously at 10 mcg/kg/min for 120 min to assess cross-tolerance from morphine to remifentanil. The antinociceptive effects on somatic and visceral nociceptive stimuli were measured using the tail-flick (TF) and colorectal distension (CD) tests, respectively. The antinociceptive efficacy was evaluated by converting the response threshold to the percentage maximal possible effect (%MPE).

Results: Remifentanil increased the %MPE in the morphine and saline groups in both the tests; however, the increase in %MPE was attenuated significantly in the morphine group compared with that in the saline group at 60, 90, and 120 min (all P < 0.01) in the TF test and at 90 and 120 min in the CD test (all P <0.05).

Conclusion: Our results indicate that morphine-tolerant rats exhibit cross-tolerance to remifentanil's acute antinociceptive effects on somatic and visceral stimuli. Cross-tolerance to remifentanil should be considered in the perioperative management of patients using morphine.

Keywords: cross-tolerance; morphine; remifentanil; somatic; visceral.

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Conflict of interest statement

Dr Hideaki Mori reports grants from Japan Society for the Promotion of Science, during the conduct of the study; personal fees from Nihon Kohden, outside the submitted work. Dr Tatsuya Hashimoto reports personal fees from Shionogi, Daiichi Sankyo, and Hisamitsu, outside the submitted work. Dr Yoji Saito reports lecture fees from Daiichi Sankyo, Shionogi, Phizer, Nipponzoki, Kyowa Kirin, Terumo, Mundipharma, and Nihon Kohden, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Timeline of the experimental schedule.
Figure 2
Figure 2
Timeline of the experimental procedures for Experiments 1 (A) and 2 (B).
Figure 3
Figure 3
Results of the morphine challenge tests on days 1 and 10 (Experiment 1) in the tail-flick test (A) and colorectal distension test (B). Time course effects on percentage maximal possible effect (%MPE) after 5 mg/kg morphine or saline subcutaneous injection on days 1 and 10 are presented. The %MPE was significantly lower on day 10 than that on day 1 in both the tests in the morphine group, whereas the saline subcutaneous injection did not change in either test.
Figure 4
Figure 4
Results of the assessment for cross-tolerance from morphine to remifentanil on day 12 (Experiment 2) in the tail-flick test (A) and colorectal distension test (B). The %MPE was lower in the morphine group than that in the saline group in both tests.
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