PubMed · 15233075
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Carol McLoughlin. 2004. Opioids.. https://pubmed.ncbi.nlm.nih.gov/15233075/
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RATIONALE: Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism's sensitivity to centrally acting drugs. OBJECTIVE: The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. METHODS: Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. RESULTS: In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0-30 mg/kg) and levorphanol (0.3-10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03-3.0 mg/kg), butorphanol (0.3-30 mg/kg), and nalbuphine (0.3-30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. CONCLUSIONS: These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.
RATIONALE: Functional magnetic resonance imaging (fMRI) in rats can non-invasively identify brain regions activated by physiological stimuli and the effects of pharmacological intervention on these responses. OBJECTIVES: This study was conducted to investigate the effects of systemic administration of the mu-opioid receptor agonist morphine on whole brain functional signal intensity in anaesthetised rats; to investigate whether pre-treatment with the opioid receptor antagonist naloxone blocks the effects of morphine; to determine whether pre-treatment with morphine attenuates noxious-evoked changes in whole brain functional signal intensity. METHODS: Continuous whole brain fMRI scanning was used to study brain signal intensity prior to, and following, systemic administration of morphine (5 mg/kg, n=7), systemic administration of naloxone (1 mg/kg) and morphine (n=8). Effects of pre-treatment with saline (n=5) or morphine (5 mg/kg, n=5) on formalin (5%, intraplantar)-evoked changes in signal intensity were determined. Data were processed using SMP99 with fixed-effects analysis (p<0.05). RESULTS: Morphine produced significant positive bilateral increases in signal intensity in the cingulate cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05), and these effects were blocked by naloxone. Intraplantar injection of formalin produced a significant positive increase in signal intensity in the cingulate cortex, somatosensory cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05). Morphine attenuated formalin-evoked increases in signal intensity in the PAG, amygdala, hypothalamus and cingulate cortex. CONCLUSION: Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.
Continuous opioid agonist treatment produces tolerance and in some cases mu opioid receptor (muOR) down-regulation. Previous studies indicate that down-regulation of muOR is more likely with high-efficacy opioid agonists (e.g., etorphine), whereas lower efficacy agonists (e.g., morphine) do not regulate muOR density. It has been suggested that muOR down-regulation may depend upon increases in Dynamin-2 (DYN-2) proteins. Therefore, the present study examined the effect of various infusion doses of etorphine on muOR density, DYN-2 protein, and DYN-2 mRNA abundance in mouse spinal cord. Mice were implanted sc with an osmotic pump that infused etorphine (50-250 microg/kg/day). Controls were implanted with inert placebo pellets. At the end of 7 days, mice were sacrificed, spinal cord removed and processed for radioligand binding, quantitative Western blotting, or RT-PCR assay. Results indicate that etorphine induced dose-dependent regulation of muOR density, DYN-2 proteins, and mRNA abundance in mouse spinal cord. Higher infusion doses significantly down-regulated muOR density, increased DYN-2 protein abundance, and decreased DYN-2 mRNA. Analysis of these results indicated a significant correlation between muOR down-regulation and DYN-2 abundance in mouse spinal cord. Taken together, muOR regulation may depend on changes in DYN-2 abundance induced by high-efficacy opioid agonists in mouse spinal cord.