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. 2016 Dec;24(6):485-495.
doi: 10.1037/pha0000097.

Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice

Harshini Neelakantan  1 , Sara Jane Ward  2 , Ellen Ann Walker  1
Affiliations

Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice

Harshini Neelakantan et al. Exp Clin Psychopharmacol. 2016 Dec.

Abstract

This study evaluated the hypothesis that a paclitaxel treatment regimen sufficient to produce mechanical allodynia would alter sensitivities of male and female mice to the conditioned rewarding and reinforcing effects of morphine. Saline or paclitaxel were administered on Days 1, 3, 5, and 7 in male and female C57Bl/6 mice to induce morphine-reversible mechanical allodynia as measured by the Von Frey filament test. Paclitaxel treatment did not change sensitivity to morphine conditioned place preference (CPP) relative to saline treatment in either male or female mice. Morphine produced peak self-administration under a fixed ratio-1 (FR1) schedule of reinforcement for 0.03 mg/kg morphine per infusion in female mice and 0.1 mg/kg morphine per infusion in male mice. During the progressive ratio experiments, saline treatment in male mice decreased the number of morphine infusions for 12 days whereas the paclitaxel-treated male mice maintained responding for morphine similar to baseline levels during the same time period. However, paclitaxel did not have an overall effect on the reinforcing efficacy of morphine assessed over a limited dose range during the course of the repeated self-administration. These results suggest that the reward-related behavioral effects of morphine are overall not robustly altered by the presence of paclitaxel treatment under the current dosing regimen, with the exception of maintaining a small yet significant higher baseline than saline treatment during the development of allodynia in male mice. (PsycINFO Database Record

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Paclitaxel treatment does not alter the rewarding effects of morphine in the conditioned place preference assay in male (panel A) or female (panel B) mice. Abscissa: Saline (Sal) or doses of morphine expressed as mg/kg. Ordinate: Preference score, time spent in the drug – vehicle paired sides on the test day in seconds (s). Each point represents the mean preference score ± SEM (n=8/group for morphine, n=16/group for saline). ^, significantly different than saline-conditioned place preference p<0.05; *, significantly different than saline and 0.03 mg/kg morphine-conditioned place preference: p<0.05.
Figure 2
Figure 2
An inverted-U shaped dose-response for morphine under an FR1 schedule of reinforcement in male (filled circles) and female (open squares) mice. Abscissa: Saline (Sal) or unit dose of morphine expressed as mg/kg per infusion. Ordinate: Response rate expressed as the mean number of infusions per 2 h ± SEM (n=5–18/group). Significantly different than saline responding: *, p<0.05; **, p<0.01.
Figure 3
Figure 3
Paclitaxel treatment maintained responding for morphine under a PR schedule in male mice responding for 0.1 mg/kg per infusing compared to saline treatment (panel A) but not in female mice responding for 0.03 mg/kg per infusion (panel B). Abscissa: Baseline (Bl) prior to stating paclitaxel injections, day after first saline (filled symbols) or paclitaxel (closed symbols) injection. Paclitaxel injections occurred on days 1, 3, 5, and 7. Left ordinate: Breakpoint (defined as the number of infusions per session); Right ordinate: Corresponding total cumulative number of responses required in the PR schedule. Each data point represents mean ± SEM (n=6–15/group).
Figure 4
Figure 4
Paclitaxel treatment did not alter morphine dose-response curves under a PR schedule of responding in either male (panel A) or female (panel B) mice. Abscissa: Unit doses of morphine expressed as mg/kg per infusion. Left ordinate: Breakpoint (defined as the number of infusions per session); Right ordinate: Corresponding total cumulative number of responses required in the PR schedule. Each data point represents mean number of infusions achieved in the 4 h session ± SEM (n=6–15/group).
Figure 5
Figure 5
Mechanical allodynia develops after 5 days of treatment with 8 mg/kg paclitaxel treatment (panels A, C) and is reversed by morphine (2.5–10 mg/kg) (panels B, D) in only the paclitaxel-treated male (upper panels) and female (lower panels) mice. Abscissa: Time points prior to (D0) and after initiation of paclitaxel treatment on days 5 and 8) (panels A and C); baseline (Bl) and morphine dose expressed as mg/kg (panels B and D) on days 11–27. Ordinate: Threshold of sensitivity to the mechanical stimulus (g). Bars represent the mean ± SEM for paw withdrawal thresholds in g; n=8 per group. Significantly different than baseline: *, p<0.03; **, p<0.004; ***, p<0.0001; ^, p<0.02; ^^, p<0.006.
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