Opioids are the most effective treatment for pain, but a host of side effects such as lethal overdoses limits their use. Endomorphins are endogenous opioid ligands that show promise as a basis for safer analgesics. Several EM analogs were developed to provide equal analgesic effects compared to morphine, with reduced respiratory depression, motor, cognitive, tolerance, and reward side effects. Tested here in reward models, morphine was compulsively self-administered and produced conditioned place preference (CPP) and locomotor sensitization after repeated injections. In sharp contrast, EM analogs were inactive in all of these models. Mechanisms for reduced tolerance and reward are proposed here. Chronic EM analog infusions produced substantially less tolerance than equi-effective doses of morphine. Morphine upregulated glial cell markers of proinflammatory activation and signaling as well as the neuronal proinflammatory peptide CGRP. By contrast, EM analogs did not produce glial or CGRP activation suggesting reduced proinflammatory side effects. In the CPP reward model, morphine produced a place preference and decreased the cell soma size of dopamine (DA) neurons in the ventral tegmental area (VTA), a critical area for reward. EM analog 4 did not produce CPP and did not change the size of these neurons in the VTA. Penetration of the blood-brain barrier (BBB) by EM analogs was confirmed by central antagonism of the antinociceptive effects of peripherally administered analogs. This work suggests that EM analogs do not promote reward behaviors and do not produce morphological changes to DA neurons in the VTA, despite BBB penetration. Therefore, the reduced tolerance and reward side effects of the analogs could be due to lack of proinflammatory effects and reduced DA neuron alterations. Finally, the subjective effects of EM analogs were tested in a drug discrimination (DD) model. During DD test sessions, rats responded on the morphine-paired lever for food when pre-injected with EM analogs, indicating that the analogs were perceived as being more similar to morphine than vehicle, despite evidence that they did not produce rewarding effects. Data shown here suggest a dual role for EM analogs in the treatment of pain and opioid addiction. / 1 / Mark R. Nilges
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_45948 |
| Date | January 2015 |
| Contributors | Nilges, Mark R. (author), Zadina, James (Thesis advisor), School of Science & Engineering Neuroscience (Degree granting institution) |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic |
| Rights | No embargo |
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