The evaluation of peptides as potential therapeutic or diagnostic agents requires the consideration of several criteria that are targeted around two axes: functionality and metabolic stability. Most often, a compromise has to be made between these mutually opposing characteristics. In this study, Derringer's desirability function, a multi-criteria decision-making method, was applied to determine the best peptide for opioid studies in a single figure-of-merit. The penetration of the blood-brain barrier (BBB) determines the biological functionality of neuropeptides in the brain target tissue, and consists of an influx and an efflux component. The metabolic stability in the two concerned tissues, i.e. plasma and brain, are taken into consideration as well. The overall selection of the peptide drug candidate having the highest BBB-drugability is difficult due to these conflicting responses as well as the different scalings of the four biological parameters under consideration. The highest desirability, representing the best BBB-drugability, was observed for dermorphin. This peptide is thus the most promising drug candidate from the set of eight opioid peptides that were investigated. The least desirable candidate, with the worst BBB influx and/or metabolic stability, was found to be CTAP. Validation of the desirability function by in vivo medical imaging showed that dermorphin and DAMGO penetrate the BBB, whereas EM-1 and TAPP did not. These results are thus consistent with those obtained with the desirability evaluation. To conclude, the multi-criteria decision method was proven to be useful in biomedical research, where a selection of the best candidate based on opposing characteristics is often required.
The opioid and serotonergic systems are closely involved in pain processing and mood disorders. The aim of this study was to assess the influence of systemic morphine on cerebral serotonin 2A receptor (5-HT 2A ) binding in dogs using SPECT with the 5-HT 2A radioligand 123 I-5I-R91150. Methods: 5-HT 2A binding was estimated with and without morphine pretreatment in 8 dogs. The 5-HT 2A binding indices in the frontal, parietal, temporal, and occipital cortex and in the subcortical region were obtained by semiquantification. Results: A significantly decreased 5-HT 2A binding index was found in the morphine group for the right (morphine, 1.41 6 0.06; control, 1.52 6 0.10) and left (morphine, 1.44 6 0.08; control, 1.55 6 0.11) frontal cortices, with P 5 0.012 and P 5 0.040, respectively. No significant differences were noted for the other regions. Conclusion: Morphine decreased the frontocortical 5-HT 2A availability, confirming an interaction between the 5-HTergic and the opioid systems. Whether this interaction is caused by decreased receptor density due to direct internalization or is the result of indirect actions, such as increased endogenous serotonin release, remains to be elucidated.Key Words: serotonin (5-HT); 5-HT 2A ; morphine; SPECT; frontal cortex Nucl Med 2012; 53:1969 53: -1973 53: DOI: 10.2967 It is well documented that there is a close interaction between the brain opioid and serotonin (5-hydroxytryptamine [5-HT]) neurotransmitter systems (1-3). Activation of the m-opioid receptor system leads to 5-HTergic changes, including increased release of synaptic 5-HT, as was shown in several brain regions and in the spinal cord in various in vivo microdialysis studies (1,2). Furthermore, pharmacologic and behavioral studies pointed out that the 5-HTergic system is implicated in spinal pain transmission, modulation, and control and particularly in the mediation of opioid analgesia (3,4). Morphine-induced analgesia is thought to rely in part on the indirect activation of descending inhibitory 5-HTergic pathways (3). Consequently, antidepressants that inhibit 5-HT reuptake, such as fluvoxamine and fluoxetine, are also known to have analgesic properties, especially in chronic pain states (5,6). JBeside its role in pain modulation (7-9), 5-HT 2A receptor (5-HT 2A ) gained interest over the last few decades due to its involvement in several neurologic disorders in humans, including anxiety (10), depression (11), schizophrenia (12), and obsessive-compulsive disorder (13). More specifically, atypical antipsychotic drugs acting as 5-HT 2A antagonists and inverse agonists were seen to be effective in reducing the symptoms of these diseases (10,14). Because the opioid system has been shown to be involved in several of these mood disorders as well (15), the interaction between m-opioid receptors and 5-HT 2A at an emotional or cognitive level gained interest, partly with regard to common opioid side effects such as tolerance and addiction that are thought to have a 5-HTergic component as well. Consequently, several in v...
Functional imaging provides important insights into canine brain pathologies such as behavioral problems. Two (99m) Tc-labeled single photon emission computed tomography (SPECT) cerebral blood flow tracers-ethylcysteinate dimer (ECD) and hexamethylpropylene amine oxime (HMPAO)-are commonly used in human medicine and have been used previously in dogs but intrasubject comparison of both tracers in dogs is lacking. Therefore, this study investigated whether regional distribution differences between both tracers occur in dogs as is reported in humans. Eight beagles underwent two SPECT examinations first with (99m) Tc-ECD and followed by (99m) Tc-HMPAO. SPECT scanning was performed with a triple head gamma camera equipped with ultrahigh resolution parallel hole collimators. Images were reconstructed using filtered backprojection with a Butterworth filter. Emission data were fitted to a template permitting semiquantification using predefined regions or volumes of interest (VOIs). For each VOI, perfusion indices were calculated by normalizing the regional counts per voxel to total brain counts per voxel. The obtained perfusion indices for each region for both tracers were compared with a paired Student's T-test. Significant (P < 0.05) regional differences were seen in the subcortical region and the cerebellum. Both tracers can be used to visualize regional cerebral blood flow in dogs, however, due to the observed regional differences, they are not entirely interchangeable.
To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points.
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