Invertebrate opiate immune and neural signaling.
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Amino Acid Sequence↗
Biomedical subjects
Patrick Cadet
Publications and source records attributed to Patrick Cadet.
The nongenomic protective effects of estrogen on the male cardiovascular system: clinical and therapeutic implications in aging men.
Although the preponderance of studies investigating the effects of estrogen on vasomotor tone and function have focused on women, a number of recent studies have intriguingly shown that estrogen's rapid vasodilatory properties is also preserved in men. Unlike classical steroid transcription mediated pathways, estrogen's acute vasodilatory effect is mediated by calcium dependent cell surface estrogen receptors that stimulate constitutive endothelial nitric oxide synthase (eNOS) activity. The transient release of eNOS derived nitric oxide exerts profound physiological effects on the vasculature exerting a state of cellular inhibition (i.e. vasodilation). Thus, the partial or complete attenuation of this rapid signaling system can promote endothelial dysfunction, an early pathophysiological event in atherosclerotic development. Consequently, human males experiencing age-related declines in testosterone and aromatase derived estradiol plasma levels may lose a vital cardioprotective mechanism that preserves proper endothelial function. Therapeutic strategies to preserve basal nitric oxide levels through the maintenance of normal physiological estradiol levels may confer cardiovascular benefits to aging males.
Adult↗
Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response.
Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution. Cannabinoid receptor-1 expression (CB1), anandamide, and anandamide amidase have been found in invertebrates. Furthermore, this signaling system is coupled to constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO) release in both vertebrates and invertebrates, thereby regulating neural, immune, and vascular-like functions in these divergent organisms. In human endothelial cells from various blood vessels, CB1 immunoreactive components are present as is its coupling to anandamide-stimulated cNOS-derived NO production, which exerts an autoregulatory role on cNOS release. The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways, and interactions between NO and the sympathetic nerve system are of importance, i.e, norepinephrine. Here, a possible association of NO and endocannabinoid signaling with the relaxation response, a physiological counterpart of the stress response, may exist.
Animals↗
Cyclic exercise induces anti-inflammatory signal molecule increases in the plasma of Parkinson's patients.
It has been known for many years that immune system alterations occur with Parkinson's disease (PD). Changes in lymphocyte populations in cerebrospinal fluid and blood, immunoglobulin synthesis, and cytokine and acute phase protein production have been observed in patients with PD. Hence, there is evidence for inflammation. In this report we demonstrate that cyclic exercise over months results in a significant increase in the rise of plasma anti-inflammatory signal molecules, such as interleukin-10 and adrenocorticotropin. Additionally, endogenous plasma morphine levels increase with the duration of the cyclic exercise protocol. Morphine is identified and quantified by high performance liquid chromatography coupled to electrochemical detection and nano electro-spray ionization double quadrupole orthogonal acceleration time of flight mass spectrometry. Proinflammatory cytokine, i.e., interleukin-1, interleukin-6, plasma levels did not increase. These results matched with those reported previously, demonstrating enhanced motor skills and mood elevation with this cyclic exercise protocol, suggest that this protocol induces the formation of anti-inflammatory signal molecules, which appear to be associated with alleviation of some of the clinical characteristics of PD.
Adrenocorticotropic Hormone↗
Cold stress alters Mytilus edulis pedal ganglia expression of mu opiate receptor transcripts determined by real-time RT-PCR and morphine levels.
Previous pharmacological, biochemical and molecular evidence prove that mu-subtype opiate receptors and opiate alkaloids, i.e. morphine, are present in the ganglionic nervous system of the mollusk Mytilus edulis (bivalve). We now present molecular evidence on the effect of rapid temperature changes on mu opiate receptor expression and morphine levels. Using primers, a labeled Taq-Man probe derived from the human neuronal mu1 opiate receptor, and real-time RT-PCR to measure the expression of mu transcripts from Mytilus pedal ganglia, we observe, in animals placed in cold water from room temperature, an enhanced morphine and morphine 6 glucuronide level in addition to a decrease in mu opiate receptor gene expression. This study provides further evidence that mu-type opiate receptors and morphine are expressed in mollusk ganglia and appear to be involved in physiological processes responding to thermal stress.
Animals↗
Tonal nitric oxide and health--a free radical and a scavenger of free radicals.
Basal/tonal nitric oxide (NO) production helps maintain particular microenvironments, i.e., vascular. Besides NO's function in controlling the activation state of various tissues such as immune cells, its presence appears to modulate other free radical levels, i.e., H2O2, in these same tissues and indeed these processes may be one and the same. Thus, by being a free radical, along with the ability to scavenge other free radicals, NO is placed in a pivotal regulatory position. We surmise that in the absence of adequate NO release other free radicals may go 'unchecked' and, therefore, initiate tissue damage. Furthermore, under these circumstances, proinflammatory events will occur due to heightened cell sensitivity and a diminished control of NF-kappaB. In an excess situation, and one without an appropriate circumstance, i.e., microbial action, NO may become the harmful agent. Hence, balancing basal NO production in body compartments may represent a fundamental process in maintaining general, long-term health.
Animals↗
Tonal nitric oxide and health: anti-bacterial and -viral actions and implications for HIV.
Nitric oxide has been shown to have important physiological regulatory roles, i. e, vasodilation, neurotransmitter release, etc. Now, we review its role as an antibacterial and antiviral agent. Nitric oxide has also been identified as an important factor in the development of non-specific immunity. And accordingly, nitric oxide synthase (NOS), the catalytic enzyme producing nitric oxide, is a key element in the protective activities of nitric oxide. The expression of inducible (i) NOS is regulated by cytokines. iNOS-derived nitric oxide was found to contribute to both early and late phases of antibacterial activity. Enzymes, such as proteases (reverse transciptases, and ribonucleotide reductase, etc.) containing cysteine residues, appear to be targets for nitric oxide nitrosylation, as well as viral-encoded transcription factors that are involved in viral replication. It would appear that this multifunctional signaling molecule is not only involved with signaling between cells, it also appears to maintain the immediate environment free of microbial agents.
Animals↗
Direct assessment and diminished production of morphine stimulated NO by diabetic endothelium from saphenous vein.
AIM: To directly measure in real time basal and stimulated levels of NO released from human saphenous vein endothelium and to quantify the expression of the mu opiate receptor, which has been linked with NO release. METHODS: Saphenous vein segments from patients with type 2 diabetes (n=12) and patients without diabetes (n=8) were obtained. The release of NO was measured directly from the endothelium using a NO-specific amperometric probe. N(Omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 mmol/L), a NO synthase (NOS) inhibitor, or morphine (1 mumol/L), a stimulant, was administered and the measurements were repeated. Values were reported relative to the mean initial measurement of NO release from diabetic endothelium, which was defined as the relative zero level of NO release. A RT-PCR was then performed on the endothelium to measure mu opiate receptor expression. RESULTS: Diabetic patients (n=12) showed a relative and significantly diminished basal level of released NO, (0.049+/-0.012) nmol/L, compared with non diabetic patients (n=8), (0.42+/-0.12) nmol/L (P<0.05). Application of L-NAME to nonstimulated tissues resulted in no change in NO release from the diabetic group and a decrease in NO release of (0.21+/-0.09) nmol/L from the non diabetic group (P<0.05). Morphine stimulation of the diabetic endothelium resulted in a lower peak and shorter duration of NO release compared to the non-diabetic tissue, (21+/-6) nmol/L vs (38+/-4) nmol/L and (7.3+/-1.4) min vs (12.2+/-2.2) min, respectively (P<0.01). Lastly, evaluation of the mu opiate receptor expression was found to be diminished in the diabetics by 59.1 %. CONCLUSION: Maturity-onset diabetes attenuates both the constitutive basal and morphine stimulated NO release from human saphenous vein endothelium. In this study, after NOS inhibition, the actual basal NO release in diabetes was negligible. One explanation for the impaired capacity of diabetic endothelium to release NO was the diminished mu opiate receptor that was seen in diabetic endothelium.
Aged↗
A hormonal role for endogenous opiate alkaloids: vascular tissues.
The distribution of morphine-containing cells in the central nervous system, adrenal gland, and its presence in blood may serve to demonstrate that this signal molecule can act as a hormone besides its role in cell-to-cell signaling within the brain. This speculative review is the result of a literature evaluation with an emphasis on studies from our laboratory. Opioid peptides and opiate alkaloids have been found to influence cardiac and vascular function. They have also been reported to promote ischemic preconditioning protection in the heart. Given the presence of morphine and the novel mu(3) opiate receptor on vascular endothelial cells, including cardiac and vascular endothelial cells in the median eminence, it would appear that endogenous opiate alkaloids are involved in modulating cardiac function, possible at the hormonal level. This peripheral target tissue, via nitric oxide coupling to mu opiate receptors, may serve to down regulate the excitability of this tissue given the heart's high performance state as compared to that of the saphenous vein, a passive resistance conduit. With this in mind, morphine and other endogenous opiate alkaloids may function as a hormone.
Alkaloids↗
The blueprint for stress can be found in invertebrates.
Through an extremely complicated equilibrium called homeostasis, all living organisms maintain their survival in the face of both externally and internally generated "stimuli". This apparent harmony is constantly challenged. Survival through successful adaptation is maintained as close to steady state as possible by adaptive responses, which may also be called perturbation responses since they have a constitutively defined dynamic capacity, i.e., an immediate limit, in a series of balancing and feedback activities reflecting an astounding array of biological, psychological and sociological behaviors. The broad spectrum of stimuli capable of engaging this protective response is remarkable. We define stress as a type of stimulation that is stronger and lasts for a longer duration, upsetting a typical perturbation response given its dynamic parameters. The stress response, which evolves out of the perturbation response, involves inducible signal molecules, i.e., cytokines. We surmise that the ability to exist in an ever-changing environment was a requirement for all life forms, including invertebrates and single celled organisms. It would be expected that these organisms exhibit both perturbation and stress responses. In this regard, we demonstrate that these organisms have mammalian-like signal molecule systems, i.e., opioid, and corresponding behaviors that are similar to those found in mammals with regard to both perturbation and stress responses. Thus, it would appear that these responses evolved first in simpler organisms and were then maintained and enhanced during evolution.
Adrenocorticotropic Hormone↗
Morphine down regulates human vascular tissue estrogen receptor expression determined by real-time RT-PCR.
UNLABELLED: Human vascular endothelial cells express the estrogen receptor-beta (ER-beta), which can be modulated by the opiate alkaloid morphine. OBJECTIVES: To determine if morphine is capable of down regulating the ER-beta receptor in a similar fashion as the mu opiate receptor since they are both coupled to constitutive nitric oxide synthase derived nitric oxide release. METHODS AND RESULTS: Endothelial cells obtain from human vascular tissues (saphenous vein, atria and primary saphenous vein cells) were treated with 1 uM morphine plus or minus the mu opiate receptor antagonist naloxone or CTOP (10 uM) for 24 h at 37 degrees C. Total RNA was isolated from treated and untreated primary endothelial cells, and specific primers and a probe were used to determine the ER-beta gene expression by real-time RT-PCR. Cells treated with morphine exhibited a down-regulation of ER-beta, whereas naloxone and CTOP were able to partially block the morphine effect. In addition, the 266 bp fragment generated by RT-PCR using the same primers as in the real-time PCR was sequenced and revealed a 100% sequence identity as the authentic ER-beta gene sequence. CONCLUSIONS: These results indicate that ER-beta is expressed in human vascular endothelial cells, and morphine appears to regulate this receptor in a similar fashion as the mu opiate receptor.
Adult↗
Effects of morphine on tumour growth.
Endogenous opiate alkaloids, such as morphine, and their peptide counterparts have been implicated in a wide variety of pharmacological and physiological functions. In addition to their use in the treatment of pain, opioids, appears to be important in the growth regulation of normal and neoplastic tissue. This review will focus on the influence of endogenous and exogenous opioids on tumour growth, with emphasis on immunoregulatory and antiproliferative mechanisms.
Analgesics, Opioid↗
Effects of cold stress on morphine-induced nitric oxide production and mu-opiate receptor gene expression in Mytilus edulis pedal ganglia.
OBJECTIVES: Subjecting the marine bivalve Mytilus edulis to an immediate temperature change has been shown to rapidly alter the animals' ganglionic monoamine levels, as well as its ciliary activity. Recently, we extended this observation to include the organism's ganglionic mu opiate receptor and morphine levels. In the past, we demonstrated that M. edulis ganglionic mu receptors exposed to morphine was coupled to the immediate release nitric oxide (NO). In this study, we measured morphine-induced NO release in M. edulis subjected to acute cold stress. METHODS: NO release was monitored with an NO-selective microprobe. Temporal changes in mu opiate receptor expression were also examined over 24 hours. RESULTS: In this study, we demonstrate that after 12h cold exposure (4 degrees C from 24 degrees C), the estimated relative mu opiate receptor (MOR) gene expression in M. edulis pedal ganglia, measured by real-time PCR, did not differ significantly from the control group (1.23+/-0.25, p>0.05). However, the measured M. edulis pedal ganglia MOR expression demonstrated that ganglia significantly (0.77+/-0.05, p<0.001) down regulated their mu opiate receptor mRNA expression after 24h exposure to the cold water. The mean value for control animal (24 degrees C, n=14) morphine-stimulated NO release was 36.7 +/- 9.8 nM. Morphine additions to cold-treated tissues (4 degrees C, n=7) produced an average of 6.7 +/- 4.9 nM NO, which was a statistically significant difference between 25 degrees C and 4 degrees C animals (p=0.025). CONCLUSION: The study further demonstrates that mu opiate receptor expression is coupled to NO release.
Animals↗
17-beta estradiol down regulates ganglionic microglial cells via nitric oxide release: presence of an estrogen receptor beta transcript.
OBJECTIVES: In earlier studies we have demonstrated that 17-beta-estradiol and an estrogen cell surface receptor can be found on various human cells where they are coupled to nitric oxide release. We also demonstrated the presence of estrogen signaling in Mytilus edulis ganglia. In the present report, we sought to determine a function for these ganglionic estrogen receptors, transcending a reproductive role for estrogen. MATERIAL & METHODS: Ganglionic microglial egress from excised pedal ganglia was examined microscopically following pharmacological treatments designed to determine a role for 17-beta-estradiol in microglial regulation via nitric oxide. Additionally, we examined the tissue by RT-PCR and sequence analysis for the estrogen receptor beta gene. RESULTS: In ganglia incubated with varying concentrations of 17-beta-estradiol-BSA there is a significant drop in microglial egress at the 24 hour observation period (58.7 +/- 7.4 vs. 17-beta-estradiol-BSA exposed = 14.7 +/- 1.5; P<0.01), which can be antagonized by tamoxifen and significantly diminished by L-NAME, a nitric oxide synthase inhibitor. By RT-PCR and sequence analysis Mytilus edulis pedal ganglia was found to express a 266 bp fragment of the estrogen receptor-beta gene, which exhibits 100% sequence identity with the human counterpart. CONCLUSION: These data suggest that 17-beta-estradiol-BSA is working on estrogen cell surface receptors since 17-beta-estradiol-BSA does not enter the cytoplasm and that these receptors are coupled to constitutive nitric oxide release. This study demonstrates that 17-beta-estradiol can down regulate microglial fMLP induced activation and activation following ganglionic excision.
Animals↗
The presence of 17-beta estradiol in Mytilus edulis gonadal tissues: evidence for estradiol isoforms.
OBJECTIVES: In earlier studies, we demonstrate that 17-beta -estradiol and an estrogen cell surface receptor can be found on various human cells, i.e., vascular endothelial, monocytes, and granulocytes, where they are coupled to nitric oxide release. We further demonstrated this phenomenon in the marine mussel Mytilus edulis ganglionic tissues. In the present report we sought to determine if estrogen can be found in M. edulis reproductive tissues. MATERIAL & METHODS: We determined the presence of 17-beta -estradiol via high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA) in the animals gonads. This substance was further identified via nanoelectro-spray ionization quadrupole time of flight mass spectrometry (Q-TOF-MS). RESULTS: 17-beta -estradiol was identified and quantified in Mytilus gonads. Interestingly, we also determined that estradiol isoforms also were present in this tissue. CONCLUSION: These data demonstrate that 17-beta-estradiol and an estradiol isoform is present in M. edulis gonadal tissues, suggesting that they have functions related to reproduction. This further suggests that estrogen's association with reproductive activities has a long evolutionary history and that this association began in invertebrates.
Animals↗
Immunocytes modulate ganglionic nitric oxide release which later affects their activity level.
Pedal ganglia excised and maintained in culture for up to 2 h, release NO at low levels. The range can vary between 0 to 1.1 nM. Non-stimulated immunocytes do not significantly stimulate ganglionic NO release when incubated with pedal ganglia. However, ganglia exposed to immunocytes that had been previously activated by a 30 min incubation with interleukin 1 beta, release NO significantly above basal levels. In these experiments, 91 +/- 2.5% of the non-stimulated immunocytes exhibited form factors in the 0.72 to 0.89 range (sampled prior to ganglionic addition), whereas 62 +/- 10.3% of the interleukin 1 beta stimulated immunocytes had form factors in the 0.39 to 0.49 range, demonstrating activation. Addition of the nitric oxide synthase inhibitor, L-NAME (10(-4) M), inhibited basal ganglionic NO release as well as that initiated by exposing the ganglia to activated immunocytes. Interestingly, non activated immunocytes, following ganglionic exposure, exhibited activity levels in the 13% range, representing a non significant increase. Cells exposed to interleukin 1 beta had a 65% activity level at the beginning of the experiment, followed by a drop of activity to 19 +/- 3.2% after ganglionic exposure. Repeating this last observation in the presence of L-NAME (10(-4) M), brought the activity level of the immunocytes back to the pre-ganglionic exposure level of activity, demonstrating that ganglionic NO was involved in down regulating immunocyte activity.
Animals↗