Opioids are effective analgesics for treating moderate to severe pain, however, chronic opioid use results in the development of opioid tolerance. This tolerance to opioids causes the need over time for increased doses of opioids to achieve the same pain-relieving effect. Clinical evidence suggests that East Asians are more responsive to opioids and possibly resistant to opioid tolerance. This is important to study since understanding the molecular mechanism of opioid tolerance may allow for design of more effective therapeutics without this unwanted side-effect.Here we suggest an inactivating point mutation in the enzyme aldehyde dehydrogenase 2 (ALDH2) that affects ~560 million East Asians. Known as ALDH2*2, this point mutation reduces the enzymatic activity by >60% in heterozygotes. The ALDH2 enzyme is well-known to metabolize reactive aldehydes and also metabolizes drugs such as nitroglycerin and chemotherapeutics. However, whether this enzyme is responsible for the decreased opioid tolerance seen in East Asian patients upon morphine treatment is unknown. The aim of this study it to determine whether the enzyme ALDH2 regulates opioid-tolerance. To address this question, we developed ALDH2*2 mice, that mimic the ALDH2 point mutation found in the East Asian population and Alda-1, a small molecule that selectively activates ALDH2. The specific aims are to a) investigate whether ALDH2*2 mice respond differently to the analgesic effect of morphine and morphine tolerance; b) evaluate whether ALDH2*2 mice display different opioid receptor internalization with chronic morphine administration; c) investigate whether the chronic use of morphine induces neurotoxicity by measuring the toxic aldehyde levels (DarkZone method) and evaluating the neuronal mitochondrial function. Oliceridine, a µ receptor G protein pathway selective modulator that do not induce tolerance/MOR internalization will be used as control. This basic biological mechanism has, if elucidated, profound implications for treating pain and provide a scientific basis for improved pain management with opiate analgesics. To this means, our findings can potentially assist with reducing pain and unwanted opioid side effects, leading to an improved quality of life and a reduction in hospital costs.
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