Opioid drugs are widely used for pain relief, but their clinical utility is seriously limited by adverse effects, such as the risk of addiction. Opioid analgesics have been overused for many years; however, a huge increase in their use in the past few decades has led to a worldwide opioid epidemic – an alarming medical, social and economic problem. Therefore, searching for effective and nonaddictive opioids is a challenge for pharmacological research.
Based on studies in transgenic animal models, it is assumed that at least some opioid adverse effects are mediated by a regulatory protein, β-arrestin 2. This protein may be involved in opioid tolerance and life-threatening respiratory depression. Therefore, the development of an opioid agonist (acting via the μ receptor) with bias toward the G protein and minimal recruitment of the β-arrestin 2 pathway is a promising approach.
In 2016,
Manglik and colleagues reported the discovery of PZM21, a G-protein-biased μ opioid receptor agonist with a reduced side-effects profile. This discovery excited and intrigued many research groups, including my own. In
our study, published in the British Journal of Pharmacology, we aimed to further investigate this compound, drawing particular attention to its effects on addiction-like behaviour in rodents.
We showed that, unlike morphine or oxycodone, PZM21 is devoid of rewarding and reinforcing properties. Our results confirm and broaden the findings described in the Manglik et al.’s original publication. PZM21 has similar antinociceptive efficacy to conventional opioids. On the other hand, we saw that repeated treatment with PZM21 caused the development of tolerance to antinociception and physical dependence (measured by naloxone-precipitated withdrawal symptoms). Therefore, we suggest that PZM21 affects motivational and physical aspects of addictive behaviour differently.
What do these findings mean? It’s possible that this compound would not produce a ‘high’ in users. However, the fact that it does produce tolerance and withdrawal symptoms makes its potential for clinical use questionable.
We also assessed the interaction of PZM21 with morphine, with interesting results. It seems that PZM21 enhances and prolongs morphine antinociception and attenuates its rewarding properties. This observation suggests that PZM21 should be further investigated as a pharmacological tool for modulation of morphine effects. It is also worth assessing whether PZM21 can diminish more complex addictive behaviours, such as craving and drug-seeking, induced by morphine and other commonly misused drugs.
Are biased opioids the real ‘holy grail’ of opioid research? Can biased opioids avoid the pitfall of addiction? That PZM21 is not rewarding and reinforcing is unique among opioid drugs, as well as among biased agonists. Thus, both PZM21 and other opioid compounds based on the idea of biased signalling are worth investigating. With each subsequent study we are closer to the answer.
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