Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.
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SUBMITTER: Sasaki K
PROVIDER: S-EPMC8698687 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (?-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a ?-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the ?-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting ?-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression.
| S-EPMC5075030 | biostudies-literature
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.
| S-EPMC10295376 | biostudies-literature
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.
| S-EPMC4407719 | biostudies-literature
Project description:The aim of this prospective clinical trial was to compare the influence of butorphanol, buprenorphine and levomethadone on sedation quality and postoperative analgesia in horses undergoing cheek tooth extraction. Fifty horses were assigned to three groups prior to oral cheek tooth extraction. Horses were treated with acepromazine, followed by a detomidine bolus, one of the three opioids and both a nerve block and gingival anaesthesia. During the surgery, sedation was maintained with a detomidine constant rate infusion. After surgery, the quality of sedation, surgical conditions and severity of the extraction were assessed with a numerical rating scale. To evaluate differences in the quality of analgesia between the three treatments, postoperative pain was estimated with the Equine Utrecht University Scale for Facial Assessment of Pain. Additionally, several parameters that are associated with dental pain were added to this validated pain score, and blood samples were taken to measure serum cortisol. Our analysis showed lower pain scores and a greater analgesic effect with levomethadone and buprenorphine compared with butorphanol, with increased locomotor activity induced by buprenorphine. While cortisol values demonstrated higher response in horses treated with levomethadone and buprenorphine compared to butorphanol, these values could be biased by unrelated stressors.
| S-EPMC9029614 | biostudies-literature
Project description:Adenosine A(1) receptor (A(1)AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A(1)AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A(1)AR agonists, some of which are structurally related to adenosine 5'-monophosphate (5'-AMP), a naturally occurring nucleotide that itself activates A(1)AR. These novel compounds potently activate A(1)AR in several orthogonal in vitro assays and are subtype selective for A(1)AR over A(2A)AR, A(2B)AR, and A(3)AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A(1)AR knockout mice, revealing a strict dependence on A(1)AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (K(i) of 36 nM for the human A(1)AR) make this compound potentially suitable as a therapeutic.
| S-EPMC3501123 | biostudies-literature
Project description:BackgroundThe authors showed in a previous study that some novel triazine derivatives had an anti-inflammatory effect. The present study was designed to evaluate the antinociceptive effect of five out of nine compounds including two vanillin-triazine (5c and 5d) and three phenylpyrazole-triazine (10a, 10b, 10e) derivatives which showed the best anti-inflammatory effect.MethodsMale Swiss mice (25-30 g) were used. To assess the antinociceptive effect, acetic acid-writhing, formalin, and hot plate tests were used after intraperitoneal injection of each compound.ResultsAll compounds significantly (P < 0.001) reduced acetic acid-induced writhing at tested doses (50, 100, and 200 mg/kg). Also, the percent inhibition of writhing in the acetic acid test showed that at the maximum tested dose of these compounds (200 mg/kg), the order of potencies is as follows: 10b > 10a > 10e > 5d > 5c. In the formalin test, compounds 5d, 10a, and 10e showed an antinociceptive effect in the acute phase and all compounds were effective in the chronic phase. In the hot plate test, compounds 5c, 5d, and 10a demonstrated an antinociceptive effect.ConclusionsThe results clearly showed that both vanillin-triazine and phenylpyrazole-triazine derivatives had an antinociceptive effect. Also, some compounds which showed activity in the early phase of formalin test as well as in the hot plate test could control acute pain in addition to chronic or inflammatory pain.
| S-EPMC9530681 | biostudies-literature
Project description:ObjectiveAlthough opioid maintenance is a first-line approach for treating opioid use disorder (OUD), suboptimal treatment outcomes have been reported among emerging adults (EAs; 18-25 years of age). In this secondary analysis, we compared treatment outcomes between EAs and older adults (OAs; ? 26 years of age) receiving low-barrier, technology-assisted Interim Buprenorphine Treatment (IBT) during waitlist delays to comprehensive opioid maintenance treatment.MethodParticipants were 35 individuals with OUD who received IBT consisting of 12-weeks of buprenorphine maintenance with bi-monthly clinic visits and technology-assisted monitoring. At monthly follow-up assessments, participants completed staff-observed urinalysis, the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Addiction Severity Index (ASI).ResultsAt study intake, EAs (n = 10) reported greater past-year intravenous drug use and greater employment, legal, and psychiatric severity (p's < .05) compared to OAs (n = 25). Despite these initial differences, there were no significant differences in the percentages of urine specimens testing negative for illicit opioids between EA and OA participants at Study Week 4 (90 % vs. 88 %, p = .99), Week 8 (80 % vs. 76 %, p = .99) or Week 12 (60 % vs. 68 %, p = .71). Relative to their older peers, EAs also demonstrated significantly greater improvements on the BAI, BDI-II, and ASI Employment and Legal subscales (p's < .05).ConclusionsDespite presenting with greater past-year intravenous drug use and psychosocial severity relative to OAs, EAs responded favorably to the IBT intervention.
| S-EPMC7108757 | biostudies-literature
Project description:ObjectiveAcute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown.DesignRandomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations.SettingAmbulatory.SubjectsTwelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22?mg); no dose change for 1.5-12?months. Ten healthy controls.MethodsIntravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times.ResultsCold pressor responses (seconds): baseline: control 34?±?6 vs buprenorphine 17?±?2 (P?=?0.009); morphine infusion-end: control 52?±?11(P?=?0.04), buprenorphine 17?±?2 (P?>?0.5); electrical stimulation responses (volts): baseline: control 65?±?6 vs buprenorphine 53?±?5 (P?=?0.13); infusion-end: control 74?±?5 (P?=?0.007), buprenorphine 53?±?5 (P?>?0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P?=?0.03); infusion-end: control 15 (P?=?0.09), buprenorphine 12 (P?<?0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23?±?1, buprenorphine 136?±?10.ConclusionsBuprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.
| S-EPMC6329438 | biostudies-literature
Project description:The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK's mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.
| S-EPMC8037321 | biostudies-literature
Project description:Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone (1), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone (3), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5-25 mg/kg b.w.) exhibited dose-dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1-4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents.
| S-EPMC5826308 | biostudies-literature