Year: 2017
Type: dissertation
Abstract: Tobacco use is the leading cause of preventable death worldwide. Nicotine is the primary addictive component of tobacco, and repeated nicotine exposure often leads to dependence in humans. Nicotine is one of the most commonly co-used substances among polysubstance abuse patients and combined use of nicotine and other drugs of abuse, such as opioids, increases the use of one or both substances. The health consequences associated with polysubstance abuse exceed those of either drug alone. The current pharmacotherapeutic options are ineffective among opioid-substituted patients and the levels of successful smoking cessation are low. At the cellular level, nicotine and opioids have their own molecular mechanisms of action, yet both drugs increase the activity of the reward pathway by increasing dopamine transmission. The purpose of these studies was to investigate the possible effects of different opioid ligands on human neuronal nicotinic acetylcholine receptors (nAChRs) expressed in cell cultures. Our results showed that morphine has a partial agonist effect at α4β2 nAChRs, a very weak antagonist effect at α3* nAChRs and a positive synergistic effect with nicotine on α7 nAChR function. We found that methadone acts as a non-competitive antagonist (NCA) at α4β2 and α3* nAChRs. We also confirmed that methadone is a human α7 nAChR agonist. In the prolonged studies with methadone and morphine, we found that human α3*, α4β2 and α7 nAChRs are differentially regulated by prolonged exposure to methadone and morphine. Buprenorphine was shown to be a weak antagonist at α4β2, α3*, and α7 nAChRs, and codeine had a positive modulatory effect on α4β2 nAChRs and a weak NCA effect on α3* nAChRs. Oxycodone seemed to have a mixed competitive/non-competitive effect on α4β2 nAChRs and a weak NCA effect on α3* nAChRs. Tramadol was shown to be a NCA of α3* nAChRs and a weak NCA of α4β2 nAChRs. Naloxone and naltrexone were mixed competitive/non-competitive antagonists of α4β2 nAChRs, weak NCAs of α3* nAChRs and weak antagonists of α7 nAChRs. Taken together, these studies showed that many opioid ligands have effects on nAChRs that are independent of their agonist or antagonist properties at opioid receptors. These findings suggest that some effects of the nicotine opioid interaction seen in humans can be partially mediated through the receptor-level interplay of these substances. These results, together with earlier findings, highlight the complexity of different nAChRs and the multiplicity of responses to opioid ligands.
Source: Työväentutkimus Vuosikirja
Author: Reeta Talka
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2610164424