Neuro-Signals
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The development of the prototype synthetic delta-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe- Phe-OH); Tic: tetrahydroisoquinoline-3-carboxylic acid] and TIPPpsi (H-Tyr-psiTic-Phe-Phe-OH) by Schiller and coworkers was followed by extensive structure-activity relationship studies, leading to the emergence of numerous analogs that are of pharmacological interest. Eight novel diastereomeric compounds in this peptide family were designed, prepared, and tested biologically to gain structure-activity relationship information. The new multisubstituted tetrapeptide analogs contain both a 2',6'-dimethyltyrosine residue at the N-terminus and beta-methyl-cyclohexylalanine at the third position as replacements for the original first tyrosine and the third phenylalanine, respectively. ⋯ The potency and delta- versus mu-opioid receptor selectivity were evaluated by in vitro radioreceptor-binding assays, while the intrinsic G-protein-activating efficacy of these analogs was tested in [35S]GTPgammaS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing mu- or delta-opioid receptors. The analogs showed delta-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed mu-agonist/delta-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. These results constitute further examples of the influence of beta-methyl substitution and C-terminal amidation on potency, selectivity, and signal transduction properties of TIPP-related peptides as well as they represent valuable pharmacological tools for opioid research.
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The condition of pain after spinal cord injury (SCI) affects the life quality of nearly 70% of individuals with SCI. Clinical studies over the past decade have provided important insights into the complexities of the clinical and psychosocial characteristics of this debilitating consequence of SCI. The use of experimental models developed to study at-level or below-level pain has provided an appreciation for the mechanism(s) responsible for the onset and progression of these conditions. Important to the studies related to SCI pain has been the focus on the molecular, biochemical, anatomical, and functional consequences of SCI that have identified potential therapeutic targets for the design of novel treatment strategies.
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Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. ⋯ Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.