Endogenous morphine modulates acute thermonociception in mice

Guarna, Massimo; Bianchi, Enrica; Bartolini, Alessandro; Ghelardini, Carla; Galeotti, Nicoletta; Bracci, Luisa; Neri, Carla; Sonetti, Dario; Stefano, George B.

doi:10.1046/j.0022-3042.2001.00708.x

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…Endogenous morphine has been implicated in the regulation of pain and in weakening the memory of a nociceptive experience, which plays a similar role as its exogenous counterpart (Charlet et al, 2010;Guarna et al, 2002Guarna et al, , 2004Guarna et al, , 2005. However, the mechanism of action of endogenous morphine in the CNS remains unknown, and the presence of endogenous morphine-like compounds in nondopaminergic cells and in regions of the spinal cord not usually involved in pain modulation allows for exciting future studies to examine and extend the role of these endogenous opiates beyond their analgesic functions.…”

Section: Discussionmentioning

confidence: 97%

Localization of endogenous morphine‐like compounds in the mouse spinal cord

Laux¹,

Delalande²,

Mouheiche³

et al. 2012

J of Comparative Neurology

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Morphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on endogenous morphine-like compound distribution in the adult mouse brain has been recently improved, and new hypotheses have been suggested about the potential implications in brain physiology. Endogenous morphine-like compounds have been shown to be synthesized in the spinal cord, but their localization is unknown. Here we describe the distribution of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the adult mouse spinal cord using a well-validated antibody. By using different microscopy approaches, we found the presence of morphine, codeine, or morphine glucuronides in γ-aminobutyric acid (GABA)-ergic neurons and astrocytes of the spinal cord. Whereas GABAergic neurons containing endogenous morphine-like compounds were located primarily in the ventral horn, astrocytes that were labeled for morphine-like compounds were found throughout the gray matter and the white matter. Our study demonstrates the possibility that endogenous morphine-like compounds in the central nervous system have other functions beyond their analgesic functions.

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Section: Discussionmentioning

confidence: 97%

Localization of endogenous morphine‐like compounds in the mouse spinal cord

Laux¹,

Delalande²,

Mouheiche³

et al. 2012

J of Comparative Neurology

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“…Guarna et al. [7] investigated the effects of depletion of endogenous morphine on nociceptive transmission. The immunoneutralization of endogenous morphine from brain extracellular spaces was obtained through the intracerebroventricular administration of affinity purified antimorphine IgG to mice, which then underwent a hot plate test.…”

Section: Discussionmentioning

confidence: 99%

The Impact of CYP2D6 Genetic Polymorphisms on Postoperative Morphine Consumption

et al. 2009

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A B S T R A C TBackground. Endogenous morphine-like compounds have been identified in humans and are released in response to stress. Human monocytes and granulocytes express the m opiate receptor, m3, which is morphine selective but opiate peptide insensitive. Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. We theorized that ultrarapid (UM) CYP2D6 metabolizers may have an enhancement of their endogenous pain modulating mechanisms.Methods. After institutional review board approval, a previously developed surgical patient database was evaluated for information concerning CYP2D6 genotypes and morphine consumption. One hundred forty-two patients were found to have adequate information to be included in this current analysis. The study group was divided, based on morphine consumption, into two subgroups: low morphine consumers (LMC) (Յ10 mg/4 h, N = 80) and high morphine consumers (HMC) (>10 mg/4 h, N = 62). DNA was extracted from blood in all patients and was genotyped by the Amplichip (Roche, Pleasanton, CA) to determine the specific CYP2D6 genotypes.Results. CYP2D6 UM were found to occur more frequently in the LMC group than in the HMC group (8/80 vs 0/62, P = 0.0091). No significant differences were noted for the poor, intermediate, or extensive metabolizers. Conclusions.Our current results suggest that CYP2D6 UM appear to require less morphine in the acute postoperative period compared with other CYP2D6 metabolizer groups. One possible mechanism for this observation is that CYP2D6 UM may have higher efficiency in synthesizing endogenous morphine compared with other metabolizers, thus increasing endogenous pain modulation and reducing the need for exogenous morphine.

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“…Different experiments have suggested that endogenous morphine may be implicated in nociceptive processes. Experiments carried out by Guarna et al have shown that the injection of antibodies directed against morphine into murine cerebrospinal fluid (a procedure that lowers the level of endogenous morphine in the brain) induced hypersensitivity to heat-associated pain (Guarna et al, 2002;Kieffer and Gaveriaux-Ruff, 2002). In the present study, we have shown the presence of endogenous morphine and/or morphine glucuronides and/or codeine in brain regions thought to be involved in the processing of nociceptive informations (e.g., the PAG and the raphe magnus nuclei).…”

Section: Nociceptionmentioning

confidence: 98%

“…Among the few available studies, it has been shown that endogenous morphine immunoneutralization (intracerebroventricular administration of an anti-morphine antibody) decreased thermal response latency and attenuated the anti-nociceptive effect of the MOR-selective agonist DAMGO in a hot plate test. This suggests that endogenous morphine is involved in the setting of nociceptive thresholds and in opiate-mediated pain modulation (Guarna et al, 2002). A similar immunoneutralization approach has suggested a role for endogenous morphine in the weakening of memory processes under stressful conditions .…”

Section: Introductionmentioning

confidence: 97%

Mapping of endogenous morphine‐like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells

Laux

Muller

Miehe

et al. 2011

J of Comparative Neurology

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Endogenous morphine, morphine-6-glucuronide, and codeine, which are structurally identical to vegetal alkaloids, can be synthesized by mammalian cells from dopamine. However, the role of brain endogenous morphine and its derivative compounds is a matter of debate, and knowledge about its distribution is lacking. In this study, by using a validated antibody, we describe a precise mapping of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the mouse brain. First, a mass spectrometry approach confirmed the presence of morphine and codeine in mouse brain, but also, of morphine-6-glucuronide and morphine-3-glucuronide representing two metabolites of morphine. Second, light microscopy allowed us to observe immunopositive cell somas and cytoplasmic processes throughout the mouse brain. Morphine-like immunoreactivity was present in various structures including the hippocampus, olfactory bulb, band of Broca, basal ganglia, and cerebellum. Third, by using confocal microscopy and immunofluroscence co-localization, we characterized cell types containing endogenous opiates. Interestingly, we observed that morphine-like immunoreactivity throughout the encephalon is mainly present in γ-aminobutyric acid (GABA)ergic neurons. Astrocytes were also labeled throughout the entire brain, in the cell body, in the cytoplasmic processes, and in astrocytic feet surrounding blood vessels. Finally, ultrastructural localization of morphine-like immunoreactivity was determined by electron microscopy and showed the presence of morphine-like label in presynaptic terminals in the cerebellum and postsynaptic terminals in the rest of the mouse brain. In conclusion, the presence of endogenous morphine-like compounds in brain regions not usually involved in pain modulation opens the exciting opportunity to extend the role and function of endogenous alkaloids far beyond their analgesic functions.

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Endogenous morphine modulates acute thermonociception in mice

Cited by 18 publications

References 38 publications

Localization of endogenous morphine‐like compounds in the mouse spinal cord

Localization of endogenous morphine‐like compounds in the mouse spinal cord

The Impact of CYP2D6 Genetic Polymorphisms on Postoperative Morphine Consumption

Mapping of endogenous morphine‐like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells

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