Opposing mechanisms underlying differential changes in brain oxygen and temperature induced by intravenous morphine

Solís, Ernesto; Afzal, Anum; Kiyatkin, Eugene A.

doi:10.1152/jn.00445.2018

Cited by 9 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Animals were given 2 days of rest prior to the session with morphine to minimize possible consequences of previous treatments with heroin and 6-MAM. Although morphine in this study was always tested last, oxygen responses induced by the drug were very similar to previously reported responses in drug-naive rats . The total duration of a session varied from 8 to 9 h. Two hours after the last drug injection for the session, rats were injected with 0.5–0.6 mL of Equithesin.…”

Section: Methodssupporting

confidence: 70%

“…It is true that the BBB permeability of morphine is weaker than that of heroin and 6-MAM, and this could explain the much weaker oxygen responses induced by iv morphine injection in this study. While morphine has been shown to induce respiratory depression, this effect occurs at much higher drug doses . We do not discount that these effects could be much stronger if morphine appears in the brain as a product of heroin’s metabolism.…”

Section: Resultsmentioning

confidence: 89%

See 1 more Smart Citation

6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

Perekopskiy

Kiyatkin

2019

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

Heroin rapidly enters the CNS but is quickly metabolized into 6monoacetylmorphine (6-MAM) and then morphine. Although morphine is often thought to mediate heroin's neural effects, pharmacokinetic data question this view. To further understand the effects of heroin and its metabolites, oxygen sensors were used to examine changes in nucleus accumbens (NAc) oxygen levels. Heroin, 6-MAM, and morphine were all administered intravenously at two human-relevant doses (0.25 μmol/kg and 0.98 μmol/kg) in freely moving rats. Intravenous heroin induced a biphasic change in NAc oxygen, with a decrease resulting from respiratory depression and an increase resulting from cerebral vasodilation. 6-MAM caused similar but more rapid and slightly weaker effects than heroin. The stronger response to heroin can be primarily attributed to heroin's permeability and metabolism resulting in more 6-MAM in the brain. Morphine only induced weak increases in NAc oxygen. Therefore, it appears that 6-MAM is the major contributor to acute neural effects induced by iv heroin.

show abstract

Section: Methodssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 89%

6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

Perekopskiy

Kiyatkin

2019

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Two human studies have found reduced NAA in frontal gray matter in opioid addicted individuals [39,40]. Several animal studies have reported temperature changes in the nucleus accumbens following intravenous opioid administration [41][42][43]. Therefore, there is the potential for a medication confound in the present study.…”

Section: Discussionmentioning

confidence: 71%

No evidence of abnormal metabolic or inflammatory activity in the brains of patients with rheumatoid arthritis: results from a preliminary study using whole-brain magnetic resonance spectroscopic imaging (MRSI)

et al. 2020

View full text Add to dashboard Cite

Introduction/objectives Many individuals with rheumatoid arthritis (RA) report persistent fatigue even after management of peripheral disease activity. This study used whole-brain magnetic resonance spectroscopic imaging (MRSI) to investigate whether abnormal inflammatory activity in the central nervous system may be associated with such symptoms. We hypothesized that RA patients would show higher brain choline (CHO), myo-inositol (MI), and lactate (LAC), and higher brain temperature than healthy controls. We further hypothesized that the metabolite levels would be positively correlated with self-reported fatigue. Method Thirteen women with RA provided fatigue severity ratings and underwent whole-brain MRSI and a joint examination. Thirteen healthy controls (HC) provided comparison imaging and fatigue data. CHO, MI, LAC, and brain temperature in 47 brain regions were contrasted between groups using independent-samples t tests. Significant differences were determined using a false discovery rate (FDR)-adjusted p value threshold of ≤ 0.0023. Secondary analyses obtained correlations between imaging and clinical outcomes in the RA group. Results No brain metabolic differences were identified between the groups. In the RA group, fatigue severity was positively correlated with CHO in several brain regions-most strongly the right frontal lobe (r s = 0.823, p < 0.001). MI was similarly correlated with fatigue, particularly in the right calcarine fissure (r s = 0.829, p < 0.001). CHO in several regions was positively correlated with joint swelling and tenderness. Conclusions We conclude that abnormal brain metabolites are not a common feature of RA, but may been seen in patients with persistent fatigue or disease activity after conventional treatment. Key Points • Whole-brain magnetic resonance spectroscopy revealed no metabolic abnormalities in the brain in patients with rheumatoid arthritis. • Brain choline levels were correlated with fatigue severity reported by RA patients and with peripheral joint swelling and tenderness. • Brain myo-inositol levels were similarly correlated with fatigue severity in RA patients.

show abstract

“…Changes in expression of both heat and cold shock proteins have previously been reported in striatal tissue following opioid treatment [ 61 , 87 – 91 ], and our quantitative RT-PCR analysis shows that changes in expression of these genes are exacerbated by the interruption of continuous morphine exposure with naloxone. These gene expression changes could be related to opioid-induced temperature fluctuations in the nucleus accumbens [ 92 ], or a more general response to cellular stress that is independent of temperature. Striatal expression of heat shock proteins is tied to psychomotor sensitization, withdrawal, and other behavioral responses to opioids [ 89 , 93 – 98 ], supporting functional relevance of the transcriptional changes we observe.…”

Section: Discussionmentioning

confidence: 99%

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system

Lefevre

Pisansky

Toddes

et al. 2020

Neuropsychopharmacol.

View full text Add to dashboard Cite

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

show abstract

Opposing mechanisms underlying differential changes in brain oxygen and temperature induced by intravenous morphine

Cited by 9 publications

References 37 publications

6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

6-Monoacetylmorphine (6-MAM), Not Morphine, Is Responsible for the Rapid Neural Effects Induced by Intravenous Heroin

No evidence of abnormal metabolic or inflammatory activity in the brains of patients with rheumatoid arthritis: results from a preliminary study using whole-brain magnetic resonance spectroscopic imaging (MRSI)

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system

Contact Info

Product

Resources

About