Lidocaine, ketamine, and morphine depressed the median frequency resulting hypothalamic centers of neuroendocrine function, and limbic structures. . There was no significant difference () between the effects of 10 and 50 mcg/kg/min in Meloxicam failed to prevent change in MF at all stimulations. meloxicam is the most potent inhibitor of prostaglandin biosynthesis in pleural and peritoneal exudate, but Structure of meloxicam. . Relation of inhibitory activity against COX-1 and COX-2 in pretreatment with capsaicin and morphine. In this study, design, synthesis and structure–activity relationship (SAR) of various Inhibitory effect of meloxicam, a selective cyclooxygenase-2 inhibitor, and . COX-2 inhibitor celecoxib prevents chronic morphine-induced.
This possibility increased interest in the effect of chronic morphine use on the immune system. The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cellspart of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokineswhich are the tools for communication in the immune system.
This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin ILa cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells another cell of the adaptive immune system and less interleukin ILa cytokine responsible for promoting a B-cell immune response B cells produce antibodies to fight off infection.
Usually, the p38 within the dendritic cell expresses TLR 4 toll-like receptor 4which is activated through the ligand LPS lipopolysaccharide. This causes the p38 MAPK to be phosphorylated. When the dendritic cells are chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different.
The exact mechanism through which the production of one cytokine is increased in favor over another is not known.
Most likely, the morphine causes increased phosphorylation of the p38 MAPK.
This increased production of IL causes increased T-cell immune response. Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response inflammationit has been suggested that they may also influence pain.
In this way, cytokines may be a logical target for analgesic development. Noxious stimulation elicits transmission of nociceptive action potentials under general anaesthesia [ 23 ].
It activates medullary centers of circulation and ventilation, hypothalamic centers of neuroendocrine function, and limbic structures. This is exhibited as increased sympathetic tone, systemic vascular resistance, stroke volume, heart rate, cardiac output, arterial pressure, metabolic rate, and oxygen consumption as well as hyperventilation.
Endocrine responses are associated with the increase in adrenocorticotropic hormone, catecholamine, cortisol, antidiuretic, and growth hormone with parallel decrease in insulin and testosterone.
Structure-activity relationships of some opiate glycosides.
This is further accompanied by changes in electrolyte and metabolic responses [ 24 ]. Commonly used potent analgesic agents have been reported to prevent or attenuate changes in EEG variables of nociception [ 25 ] and reduce minimum alveolar concentration MAC in dogs [ 26 ]. Systemic lidocaine [ 2728 ] and ketamine [ 2930 ] are known to have analgesic effects in humans, even though lidocaine is being used traditionally as an antiarrhythmic drug when delivered systematically.
The literature regarding systemic antinociceptive effects of lidocaine and ketamine in dogs is scarce and available studies did not provide conclusive evidence on their antinociceptive effects when used as a systemic drug. A number of reports concluded that lidocaine did not have evident analgesic effects [ 3132 ]; however, there are some reports [ 33 — 35 ] that contradicted this. On a similar note, some researchers noted that ketamine did demonstrate good analgesic effects when administered systematically [ 3637 ], while a minority number of reports [ 38 ] suggested otherwise.
In fact, the data on effective analgesic concentration of ketamine is not available at all [ 39 ]. Dosages used in earlier animal studies [ 36 — 38 ] were based on human studies and were very different from each other. All these inconsistencies were attributed to the fact that nociceptive assessments in these reports were mostly based on behavioral scales. Most of these scales have not been validated for reliability, specificity, or linearity, and crucially most of the scales are based on subjective assessment of behaviour [ 4041 ].
In contrast, methods based on electroencephalography are able to not only record instantaneous response to nociception but represent an empirical approach to assess nociception in animal subjects [ 19 ]. In fact, electroencephalography has been used as a tool for objective measurement of analgesic effects of drugs in question [ 13 ].
Structure-activity relationships of some opiate glycosides.
Therefore, this study attempted to investigate the antinociceptive effects of lidocaine and ketamine administered systemically in response to electric stimulation in dogs anaesthetized with halothane using electroencephalography. It was hypothesized that systemic lidocaine and ketamine at subanaesthetic dosage are antinociceptive and therefore would depress changes in EEG spectrum in response to noxious stimulation in the dog model.
Materials and Methods 2. Six healthy adult mixed-breed female dogs weighing Dogs were judged healthy based on physical examination, hematology, and blood biochemistry. Following one-month acclimatization, dogs were subjected to six treatment protocols in a crossover Latin square design.
Wash-out period was 7 days between treatments. Anaesthesia Protocol Animals were fasted for 12 hours prior to anaesthesia with free access to water. Vaporizer was adjusted to maintain end-tidal halothane tension between 0. All animals breathed spontaneously. Animals were positioned on right lateral recumbency.
Experimental Procedure Following induction, dogs were maintained on halothane for 90 minutes to allow instrumentation and minimize residual effect of propofol. Ten minutes after the baseline stimulation, drugs were administered. The EEG data before and after the electric stimulation were collected. Then, the higher CRI doses were administered for another 20 minutes, and the EEG data collection before and after electrical stimulation was repeated. Noxious electrical stimulus was delivered with a peripheral nerve stimulator N Fisher and Paykel Healthcare international, New Zealand at 40 mA [ 42 ] and 50 Hz for 5 seconds.
The stimulus was applied to the left hind limb lateral aspect of the distal metatarsus through two subdermal needle electrodes placed subcutaneously 2 cm apart.
At the end of each experiment, halothane was disconnected and dogs were extubated when the laryngeal reflexes returned. Wuxi, Jiangsu, China were placed subcutaneously, with the inverting electrode over the zygomatic process of left frontal bone, the noninverting electrode over the left mastoid process, and the ground electrode caudal to the occipital process [ 12 ].
Care was taken to ensure that the total impedance of the circuitry was less than 5 kOhms. The electroencephalogram was recorded at a sampling rate of 1 kHz and raw EEG was resampled with low pass filter of Hz into delta frequency 0. Electroencephalogram data were collected for 10 min after electrical stimulation. Electrocardiogram was recorded continuously in the standard lead II configuration, with the negative electrode on the right forelimb and positive electrode on the left hind limb.
Analysis of the EEG data was performed offline after the completion of experiments. Power density data were derived using a Cosine-Bell function. Electrical and mechanical interference were excluded from EEG data during stimulus application by excluding wave signals five to seven seconds before and after the nociceptive electrical stimulus.
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EEG data from second blocks before to second blocks after the electrical stimulus after excluding five to seven second blocks immediately before and after the stimulus were taken for statistical analysis [ 19 ].
Heart rate was derived manually from the ECG data. Prestimulation mean heart rate PRE for each animal was calculated for a period of seconds prior to stimulation. Poststimulation mean heart rate was expressed as the percentage of PRE values and calculated at intervals of 15 seconds after 15, after 30 up to after until 5 minutes after stimulus.
Morphine - Wikipedia
Mean heart rate for the immediate 15 seconds before stimulation before 15 was calculated and expressed as percent of Statistical analysis was performed by using the SAS software package, version 9.
The datasets were compared across treatment groups and time of measurement using the ANOVA procedure. There was no significant difference in the MF at pre- and posttreatment stimulation after MLX treatment. Absolute median frequency values increased significantly after electrical stimulation compared to baseline in all treatment groups.
Ketamine and lidocaine bolus significantly depressed MF at 5 minutes posttreatment stimulus compared to pretreatment stimulus whereas they failed to prevent the rise in MF at 20 and 40 minutes. Morphine significantly prevented increases in MF at 5, 20, and 40 minutes posttreatment stimulation compared to pretreatment stimulation. Meloxicam failed to prevent change in MF at all stimulations.
Proposition 5 The first 3 amino acid sequences of beta endorphin l-try-gly-gly and the active opioid dipeptide, l-tyr-pro, as a result of a peptide turn and zwitterion bonding form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed.
This theory could be important for future analgesic drug design. Hundreds of compounds have been synthesized and tested for improvements of alkaloids derived from the opium poppy.
The simplest synthetic compounds which have extensive clinical use are meperidine and methadone. Researchers continue to search for improved analgesics with fewer side effects, increased potency, and less risk of tolerance.
The conformational similarities between morphine, meperidine, fentanyl, methadone and the endorphins are still speculative.
Although the endorphins are potent analgesics they have limited clinical use because they are inactivated during ingestion and cannot cross the blood brain barrier. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine.
General Premises of the Argument In humans, a single mu opioid receptor exists as defined by that structure of the central nervous system which binds morphine and endorphin and facilitates analgesia. The clinical, animal, experimental, and computational information pertaining to opioid and opioid peptides is vast and spans two centuries.
Some of the data may be inaccurate because laboratory and computing technologies have been refined during this time period. In order to develop a theory applicable to human pharmacology, the author chose to prioritize data in the literature. For example, conflicting activity data from homogenate receptor studies will not supercede data from in vivo human studies and conflicting structural determinations from computational chemistry will not supercede results from stereochemistry, crystallography or NMR studies.