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. 2017 May 4:349:87-97.
doi: 10.1016/j.neuroscience.2017.02.042. Epub 2017 Feb 28.

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

Sophia Samir  1 , Alexander P Yllanes  1 , Perrine Lallemand  1 , Kori L Brewer  1 , Stefan Clemens  2
Affiliations

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

Sophia Samir et al. Neuroscience. .

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 (2months, 1year, and 2years). We found that: (1) thermal pain withdrawal reflexes follow an aging-associated phenotype, with relatively longer latencies at 2months and shorter latencies at 1year, (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.

Keywords: aging; animal model; chronic pain; dopamine receptor interactions; morphine tolerance; spinal cord.

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Figures

Figure 1
Figure 1
Aging-associated changes in thermal pain withdrawal latencies after vehicle injection. A. Wild-type animals. Normal aging is associated with a decrease in withdrawal latencies from 2 months (black bar) to 1 year of age (white bar), which then increases again at 2 years of age (grey bar). B. D3KO animals. Young (2 months, black bars) and middle-aged (1 year, white bar) animals do not differ in their thermal withdrawal latencies, but as in WT, there is an increase in withdrawal latencies at 2 years of age (grey bar). Dashed / dotted lines in B refer to average values of the corresponding age groups in A. Abbreviations: 2 mo: 2 months; 1 yr: 1 year; 2 yrs: 2 years, WT: wild-type; D3KO: D3 receptor knockout. *: denotes significant difference between groups.
Figure 2
Figure 2
Effects of low and high doses of morphine on thermal pain withdrawal latencies in differently aged WT and D3KO. Displayed data represent changes in withdrawal latency compared to respective control vehicle injections, with dashed lines representing relative vehicle control levels. A. Effects of low morphine (2 mg/kg) in WT. Treatment with low morphine significantly increased thermal withdrawal latencies at all ages, and there was no significant difference between age groups. B. Effects of low morphine (2 mg/kg) in D3KO. Treatment with low morphine had no significant effect at all age, and there was no significant difference between the groups. C. Effects of high morphine (5 mg/kg) in WT. Treatment with high morphine significantly increased thermal withdrawal latencies at all ages, and this effect was significantly increased at 1 year of age over the effects at 2 months and 2 years of age. D. Effects of high morphine (5 mg/kg) in D3KO. Similar to WT, treatment with high morphine significantly increased thermal withdrawal latencies at all ages, but this effect was significantly increased at 2 months of age over the effects at 1 year and 2 years of age. Abbreviations and colors as in Figure 1. *: denotes significant difference between groups; #: denotes significant difference from vehicle control (dashed line).
Figure 3
Figure 3
Effects of the D1R antagonist, SCH 39166, on thermal pain withdrawal latencies in differently aged WT and D3KO. Displayed data represent changes in withdrawal latency compared to respective control vehicle injections, with dashed lines representing relative vehicle control levels. A. WT animals. The D3R antagonist SCH 39166 had no modulatory effect in 2 month-old animals, but increased withdrawal latencies significantly at 1 year and 2 years. The difference between 2 months and 2 years is significant. B. D3KO animals. Unlike WT, SCH 39166 strongly and significantly increased thermal pain withdrawal latencies in 2 month-old animals, but had no effect at 1 year or 2 years. The difference between 2 months and 1 year, and 2 months and 2 years is significant. Abbreviations as in Figure 1. *: denotes significant difference between groups; #: denotes significant difference from vehicle control (dashed line).
Figure 4
Figure 4
Effects of combinatory treatments of the dopamine D1R antagonist, SCH 39166, and low (2 mg/kg) or high (5 mg/kg) morphine on thermal pain withdrawal latencies in differently aged WT and D3KO. Displayed data represent changes in withdrawal latency compared to respective control vehicle injections, with dashed lines representing relative vehicle control levels. A. WT animals, SCH 39166 + low morphine. The combination of SCH 39166 and low morphine was effective across all ages in significantly increasing withdrawal latencies over the respective controls, and the increase at 2 years of age was significantly enhanced over the data at 2 months. B. D3KO animals, SCH 39166 + low morphine. In D3KO, the combination of SCH 39166 and low morphine was effective only at 2 months, but not at 1 year or 2 years. The increase at 2 months of age was significantly enhanced over the data at both 1 year and 2 years. C. WT animals, SCH 39166 + high morphine. Similar to the combination of SCH 39166 and low morphine, SCH 39166 + high morphine was effective across all ages in significantly increasing withdrawal latencies over the respective controls. Further, the increase at 1 year was significantly enhanced over that at 2 years, which in turn was larger than that at 2 months. D. D3KO animals, SCH 39166 + high morphine. In D3KO, the combination of SCH 39166 and high morphine was effective across all ages in significantly increasing withdrawal latencies over the respective controls, and there was a significant difference between 2 months, 1 year, and 2 years. Abbreviations as in Figure 1. *: denotes significant difference between groups; #: denotes significant difference from vehicle control (dashed line).
Figure 5
Figure 5
Comparison of treatments of SCH 39166 versus low or high doses of morphine. Displayed data represent changes in withdrawal latency compared to respective control vehicle injections, with dashed lines representing relative vehicle control levels. A. WT animals. Treatment with low (white bars) or high dose of morphine (grey bars) had a significantly larger effect over SCH 39166 (black bars) at 2 months and at 1 year, but at 2 years of age, SCH 39166 was more effective than low morphine, and as effective as high morphine. B. D3KO animals. Treatment with high morphine (gray bars) had at every age the strongest effect on withdrawal latencies, and at 1 year and 2 years, the effects of SCH 39166 (black bars) or low morphine (white bars) were not different from each other, and neither significantly altered withdrawal latencies. In contrast, at 2 months, SCH 39166 was highly effective, and significantly more so than low morphine. Note that the data from the 2 month-old D3KO mirrored those of the 2 year-old WT group. Abbreviations as in Figure 1. *: denotes significant difference between groups; n.s.: not significant.
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