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Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.

ABSTRACT: Butorphanol and buprenorphine are mixed opioid receptor agonist-antagonist drugs widely used as analgesics in people and animals. There are few reports concerning the interaction of multiple opioids, and their antinociceptive effects, when combined with other opioids, remain unclear. Therefore, we report the preliminary findings of the antinociceptive effects of the combined use of butorphanol and buprenorphine in C57BL/6JJcl mice. Both drugs were administered either simultaneously or in different orders. Compared with the baseline values, the tail-flick and hot-plate test latencies increased regardless of the order of administration. Furthermore, enhanced latencies were observed on administration of butorphanol followed by buprenorphine. Combined use of these drugs may not attenuate analgesic efficacy. Besides, enhancement of these effects can be obtained by changing the order of the administration of these drugs. It is necessary to further investigate the molecular basis of the underlying mechanism in future definitive studies.

SUBMITTER: Sasaki K

PROVIDER: S-EPMC8698687 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.

Sasaki Kazumasu K Ishikawa Tatsuya T Ikeda Kazutaka K Kasai Shinya S

Neuropsychopharmacology reports 20210910 4

Butorphanol and buprenorphine are mixed opioid receptor agonist-antagonist drugs widely used as analgesics in people and animals. There are few reports concerning the interaction of multiple opioids, and their antinociceptive effects, when combined with other opioids, remain unclear. Therefore, we report the preliminary findings of the antinociceptive effects of the combined use of butorphanol and buprenorphine in C57BL/6JJcl mice. Both drugs were administered either simultaneously or in differe ...[more]

PMID: 34505754

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Project description:Simple Summary Surgical procedures are routinely performed in calves, both under sedation and general anesthesia. The availability of analgesic drugs is limited in food-producing animals, making their perioperative management challenging. Few are the studies assessing the extent of pharmacological antinociception obtained when administering sedative and analgesics in cattle and the tools used are mainly qualitative. With the present study, we aimed at assessing the antinociceptive effect of butorphanol with or without detomidine in calves, using the modulation of the trigeminocervical reflex threshold as the main outcome. The trigeminocervical reflex threshold is a quantifiable nociceptive reflex that can be used to assess the modulation of pain processing. As secondary aims, physiological and behavioral effects of the administered treatments were evaluated, and the temporal profile of drug activity was described. This study provides quantitative evidence of the efficacy of butorphanol administered alone or combined with detomidine in calves. The presented findings can now contribute to optimizing the application of these drugs in clinical practice. Abstract (1) Background: The diagnostic and therapeutic procedures performed under sedation or general anesthesia in bovines are numerous. The analgesic drugs that can be legally used are few, making perioperative analgesia challenging. (2) Methods: Calves were administered butorphanol 0.1 mg kg−1 alone (SB) or combined with 0.02 mg kg−1 of a detomidine (DB) IV. The antinociceptive effect (trigeminocervical reflex threshold (TCRt)), as well as the behavioral (sedation and excitation) and physiological (heart and respiratory rate) changes were investigated. Five time windows were defined: BL (30 min pre-injection), T1 (0–30 min post-injection (PI)), T2 (31–60 min PI), T3 (61–90 min PI) and T4 (91–120 min PI). (3) Results: Both groups had a significative increase in TCRt at T1-T4 compared to the BL. The TCRt was significatively higher in DB than in SB at T1, T2 and T4. Heart rate decreased significatively in DB compared to that in BL. Calves were significantly more sedated in the DB group, and significantly more excited in the SB group compared to the BL. (4) Conclusions: Butorphanol alone has a statistically significant antinociceptive effect, but it elicits marked excitation, limiting its clinical applicability under this dosing regimen. The co-administration of detomidine eliminated the excitatory effect and induced consistent sedation and a significantly more pronounced antinociceptive effect.

Project description:The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiologic processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. In this study, we tested JZL184 [4-nitrophenyl 4-[bis(2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate] and MJN110 [2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate], MAGL inhibitors that possess increased selectivity and potency, in mouse behavioral assays of neuropathic pain [chronic constriction injury (CCI) of the sciatic nerve], interoceptive cannabimimetic effects (drug-discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid but did not affect anandamide in whole brains. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% confidence limit [CL]) values in mg/kg: MJN110 (0.43 [0.30-0.63]) > JZL184 (17.8 [11.6-27.4])] and also substituted for the potent cannabinoid receptor agonist CP55,940 [2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol] in the drug-discrimination paradigm [ED50 (95% CL) values in mg/kg: MJN110 (0.84 [0.69-1.02]) > JZL184 (24.9 [14.6-42.5])]; however, these compounds elicited differential effects on locomotor behavior. Similar to cannabinoid 1 (CB1) receptor agonists, JZL184 produced hypomotility, whereas MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although both drugs substituted for CP55,940 in the drug discrimination assay, MJN110 was more potent in reversing allodynia in the CCI model than in producing CP55,940-like effects. Overall, these results suggest that MAGL inhibition may alleviate neuropathic pain, while displaying limited cannabimimetic effects compared with direct CB1 receptor agonists.

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Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.

Publications

Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.

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