Levels Of Antinociception Research Articles

Total intravenous anaesthesia in adult mules

ObjectiveTo design an effective intravenous (IV) anaesthetic combination for field use in mules. Study designDescriptive study. AnimalsSix healthy adult mules. MethodsXylazine 1.3 mg kg−1 was administered IV and the quality of sedation was recorded. Anaesthesia was induced with 0.03 mg kg−1 diazepam and 2.2 mg kg−1 ketamine IV. Times to sternal recumbency, lateral recumbency and standing were recorded. Heart rate (HR), respiratory rate (fR), rectal temperature and haematological parameters were recorded at baseline and at 5, 15 and 45 minutes post-administration. Additionally, levels of antinociception according to responses to a pin prick test, and the quality of muscle relaxation and recovery were scored. ResultsTimes (mean ± standard deviation) to sternal and lateral recumbency were 1.3 ± 1.3 minutes and 1.8 ± 1.3 minutes, respectively, with hypertonicity of the pelvic limbs. Standing ataxia and normal gait were seen at 25.5 ± 19.0 minutes and 32.8 ± 7.9 minutes, respectively. Five minutes after induction of anaesthesia, the quality of antinociception was judged to be good to excellent (0 ± 1 on a scale of 0–3), muscle relaxation of the jaw incomplete (2 ± 1 on a scale of 1–4) and quality of recovery was very good to excellent (2 ± 1 on a scale of 1–5). The duration of anaesthesia was only 15.3 ± 1.6 minutes. Significant changes were observed only in HR at 15 minutes and fR at 5 minutes. Changes in rectal temperature and haematological parameters following anaesthesia were non-significant. Conclusions and clinical relevanceThe combination of xylazine–diazepam–ketamine provides effective short-term anaesthesia in mules under field conditions.

Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats

Oxycodone and morphine are structurally related, strong opioid analgesics, commonly used to treat moderate to severe pain in humans. Although it is well-established that morphine is a μ-opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a κ-opioid agonist (Ross and Smith, 1997). In the current study, we now show that co-administration of sub-antinociceptive doses of oxycodone (putative κ-opioid agonist) with morphine (μ-opioid agonist) to rats by both the intracerebroventricular and by systemic routes (intraperitoneal and subcutaneous), results in markedly increased (synergistic) levels of antinociception. Behaviourally, rats co-administered sub-antinociceptive doses of oxycodone and morphine were similar to control rats dosed with saline, whereas rats that received equi-potent doses of either opioid alone, were markedly sedated. These results suggest that co-administration of sub-analgesic doses of oxycodone and morphine to patients may provide excellent pain relief with a reduction in opioid-related CNS side-effects. Controlled clinical trials in appropriate patient populations are required to evaluate this possibility.11These findings are contained in the PCT patent application, PN: WO9714438-A1.

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of μ and κ agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED 50, 0.97 mg/kg), racemic U-50488H (ED 50, 0.79 mg/kg), (−)U-50488 (ED 50, 0.41 mg/kg), and another agonist PD 117,302 (ED 50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the μ opioid antagonist activity of nor-BNI is variable and that the κ opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.

Factors affecting restraint stress-induced potentiation of morphine analgesia

The analgesic effect of opioid drugs is potentiated in rats exposed to restraint stress as compared to unstressed rats. The purpose of the present study was to quantify how the following factors affect morphine-induced analgesia: habituation to restraint versus exposure to restraint for the first time, restraint stress duration, and interval from restraint to analgesic testing. Expts. 1 and 2 generated dose- and time course curves for morphine in rats exposed to one of 3 treatments: no restraint stress (NS), first exposure to 1 or 6 h of restraint (FS), or 5 days of restraint habituation followed by 1 or 6 h of restraint on the test day (HAB). Analgesia was measured by the tail-flick assay. Rats subjected to 1 h of restraint displayed dose- and time-dependent potentiation of morphine-induced antinociception compared to unstressed rats. Given 4.0 mg/kg morphine, FS-treated subjects showed 1.4- and 2.7-fold more potentiation of analgesia than HAB- and NS-treated rats, respectively. Rats restrained for 6 h prior to testing showed significant dose effect for morphine but failed to reveal significant treatment effects. Thus, increasing the duration of restraint from 1 to 6 h attenuated morphine antinociception in FS- and HAB-treated subjects to the level of NS subjects. In Expt. 3, several groups of rats underwent a single 1-h session of restraint at various time intervals prior to injection with morphine (4.0 mg/kg) and tail-flick testing. An unstressed group also receiving morphine served as control. Rats restrained at 0.5, 24, 48 and 168 h prior to testing showed significant potentiation of morphine-induced antinociception, with peak potentiation (twice the level of antinociception) occurring at 24 h after restraint. Thus, previous exposure to restraint, the duration of restraint, and interval between restraint and analgesia testing affect the degree to which stress modifies morphine-induced analgesia.