Multifunctional opioid-derived hybrids in neuropathic pain : preclinical evidence, ideas and challenges

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce effcient analgesia - which is estimated to relate to more than half of the patients-opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach

Alterations in the Activity of Spinal and Thalamic Opioid Systems in a Mice Neuropathic Pain Model

Clinical studies have reported lower effectivity of opioid drugs in therapy of neuropathic pain. Therefore, to determine the changes in endogenous opioid systems in this pain more precisely, we have studied the changes in the pain-related behavior on days 1, 14, and 28 following a chronic constriction injury (CCI) to the sciatic nerve in mice. In parallel, we have studied the changes of mu-(MOP), delta-(DOP) and kappa-(KOP) receptors, proenkephalin (PENK) and prodynorphin (PDYN) mRNA levels, as well as GTP gamma S binding of opioid receptors on the ipsi- and contralateral parts of the spinal cord and thalamus on the 14th day following CCI, as on this day the greatest manifestation of pain-related behavior was observed. On ipsilateral spinal cord, the decrease in MOP/DOP/KOP receptor and increase in PDYN/PENK mRNA expression was observed. In thalamus, MOP/DOP/KOP receptor expression decreased contralaterally. On ipsilateral side, there were no changes in PDYN/PENK or DOP/KOP receptor expression, but MOP mRNA decreased. The spinal GTP gamma S binding of MOP/DOP/KOP receptor ligands decreased on the ipsilateral side, yet the effect was less pronounced for DOP receptor ligands. In thalamus, a decrease was observed on the contralateral side for all opioid receptor ligands, especially for DOP ligand. A less pronounced decrease in GTP gamma S binding of spinal DOP ligands may indicate a weaker stimulation of ascending nociceptive pathways, which could explain the absence of decreased activity of DOP receptor ligands in neuropathy. These findings may suggest that drugs with a higher affinity for the DOP receptor will perform better in neuropathic pain. (C) 2018 Published by Elsevier Ltd on behalf of IBRO

Artificial glial-neural networks

Astrocyty są najliczniejszym typem komórek glejowych w centralnym układzie nerwowym. Przez długi czas przypisywano im wyłącznie bierną rolę strukturalną. Badania z ostatnich lat wykazały, że astrocyty pełnią zróżnicowane funkcje fizjologiczne, a także są aktywnie zaangażowane w przetwarzanie informacji poprzez generowanie fal wapniowych i uwalnianie glejoprzekaźników. Tym samym stało się jasne, że w badaniach nad funkcjonowaniem sieci nerwowej konieczne jest uwzględnienie komórek astrogleju jako nieodłącznego elementu strukturalnego i czynnościowego sieci zdolnego do modyfikowania jej działania. W niniejszej pracy porównano strukturę sieci nerwowo-glejowej (tworzonej przez astrocyty oraz dendryty szczytowe komórek piramidowych w warstwie stratum radiatum) regionu CA1 hipokampa miesięcznych oraz pięciomiesięcznych szczurów szczepu Wistar. Wykazano istotne zmniejszenie liczby astrocytów związane z wiekiem, co wskazuje na intensywną reorganizację sieci badanego regionu hipokampa w okresie postnatalnym. Dalsze badania mogą mieć na celu ustalenie, czy utrata astrocytów związana jest z optymalizacją, czy raczej zmniejszeniem efektywności działania sieci nerwowo-glejowej, i tym samym wykazać związek pomiędzy cechami strukturalnymi sieci a zdolnościami poznawczymi. Przedstawione w pracy dane ilościowe opisujące strukturę przestrzenną sieci mogą posłużyć do tworzenia innowacyjnych, kompleksowych modeli sieci nerwowo-glejowych, z wykorzystaniem już istniejących modeli matematycznych pojedynczych elementów sieci.Astrocytes are the most abundant type of glial cells that have long been considered to play a mere supportive role in the brain. Recent studies prove that astrocytes provide a variety of crucial functions in glial-neural network performance and are actively engaged in information processing due to calcium waves and gliotransmitters’ release. It became obvious that neural networks cannot exist and perform properly without astrocytes, therefore it is important to investigate the topic of brain circuits and networks’ functioning considering astroglia as an intrinsic part modifying network’s properties. In this study we compare the structure of CA1 hippocampal glial-neural network (formed by astrocytes and apical dendrites of pyramidal cells in stratum radiatum) in adolescent (1 month) and adult (5 month) Wistar rats. The study proved a significant astrocyte loss related to age, which is associated to intensive structural reorganization of neural-glial network in CA1 stratum radiatum in the postnatal life. Further studies may investigate whether astrocyte elimination is interrelated with an optimization of network performance or rather impairs its functioning, which may be tested e.g. by comparing the quantitative structure of hippocampal glial-neural network of animals exposed to enriched environment and of those housed in standard conditions. This may verify the relations between astrocyte-neuron network features and cognitive abilities. In addition, quantitative data describing networks’ spatial features presented in this study may prove useful in creating innovative complex models of realistic glial-neural networks, as only models of single network elements have been created so far

MicroRNA and its role in glioma pathogenesis and treatment

Guzy wywodzące się z gleju, zwane glejakami, są najpowszechniej występującym typem guzów mózgu. Jednocześnie najczęstszy typ glejaka, glejak wielopostaciowy, jest nowotworem najbardziej złośliwym (czwarty stopień złośliwości według klasyfikacji Światowej Organizacji Zdrowia) wiążącym się z bardzo złymi rokowaniami ze względu na intensywność proliferacji oraz wysoce heterogeniczną postać. Większość pacjentów nie przeżywa pierwszego roku od postawienia diagnozy, a standardowe terapie antynowotworowe, takie jak chemioterapia, radioterapia i chirurgia pozostają niewystarczające dla pokonania choroby. Dlatego istnieje potrzeba poszukiwania nowych rozwiązań terapeutycznych, aby glejaki mogły być efektywnie leczone.MikroRNA to małe, niekodujące cząsteczki RNA odgrywające ważną rolę w przebiegu cyklu życiowego komórki, jako że ich funkcją jest inhibicja translacji mRNA. Błędy w ekspresji mikroRNA mogą prowadzić do wielu chorób, w tym nowotworzenia. Ekspresja mikroRNA w tkance glejaka różni się od tej w zdrowej tkance mózgowej, a więc regulacja ekspresji mikroRNA w tkance glejaka powinna umożliwić zahamowanie rozwoju guza. Eksperymenty na modelach zwierzęcych potwierdzają słuszność tej hipotezy, jednak zanim terapie z użyciem mikroRNA będą mogły być stosowane u ludzi, konieczne będzie rozwiązanie szeregu problemów związanych z potencjalną terapią, takich jak sposób dostarczania mikroRNA do tkanki glejaka czy zagadnienia związane z ryzykiem biologicznym.Tumors of glial cell origin, called gliomas, are the most common primary brain tumors. Unfortunately the most frequent type of glioma, glioblastoma multiforme, is the most malignant brain tumor (IV grade malignancy according to World Health Organization’s classification) associated with a very poor prognosis due to its highly proliferative and heterogenic character. Most patients do not survive the first year after diagnosis, and typical cancer treatments, such as chemotherapy, radiotherapy and surgery remain insufficient to overcome the illness. Therefore there is a need for new therapeutic solutions so that malignant gliomas could be treated efficiently.MicroRNAs are small, non-coding RNA molecules which play a great role in cell lifecycle as their function is to inhibit mRNA translation. Errors in microRNA expression may lead to many diseases, including cancer. The microRNA expression pattern in glioma differs from that in normal brain tissue. Accordingly it seems possible that changing the expression of microRNA in gliomas could stop the tumor development. Indeed experiments on animal models show that this hypothesis is true, but before it will be possible to implement microRNAs in therapy of gliomas for humans, there are many problems to be solved, such as ways of their delivery and biological risk issues

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors