Morphine responsiveness to thermal pain stimuli is aging-associated and mediated by dopamine D1 and D3 receptor interactions

Abstract

Morphine actions involve the dopamine (DA) D1 and D3 receptor systems (D1R and D3R), and the responses to morphine change with age. We here explored in differently aged wild type (WT) and D3R knockout mice (D3KO) the interactions of the D1R/D3R systems with morphine in vivo at three different times of the animals’ lifespan (2 months, 1 year, and 2 years). We found that: 1) thermal pain withdrawal reflexes follow an aging-associated phenotype, with relatively longer latencies at 2 months and shorter latencies at 1 year, 2) over the same age range, a dysfunction of the D3R subtype decreases reflex latencies more than aging alone, 3) morphine altered reflex responses in a dose-dependent manner in WT animals and changed at its higher dose the phenotype of the D3KO animals from a morphine-resistant state to a morphine-responsive state, 4) block of D1R function had an aging-dependent effect on thermal withdrawal latencies in control animals that, in old animals, was stronger than that of low-dose morphine. Lastly, 5) block of D1R function in young D3KO animals mimicked the behavioral phenotype observed in the aged WT. Our proof-of-concept data from the rodent animal model suggest that, with age, block of D1R function may be considered as an alternative to the use of morphine, to modulate the response to painful stimuli.