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Lipo-Endomorphin-1 Derivatives with Systemic Activity against Neuropathic Pain without Producing Constipation

Figure 10

Development of tolerance to the analgesic effect of compound 3 and morphine.

Five consecutive i.v. bolus doses of compound 3 (1.6 µmol/kg) or morphine (2 µmol/kg) were administered twice-daily to CCI-rats. The mean (± SEM) ΔPWT AUC values were significantly lower for the 5th dose c.f. the 1st dose, demonstrating that antinociceptive tolerance had developed; however, the extent of tolerance developed to the analgesic effects of compound 3 was lower than that of morphine. There was no evidence of antinociceptive tolerance in the negative control group rats for treated with compound 3 for the 1st dose followed by vehicle for doses 2–4 and then compound 3 for the 5th dose. Data are the mean (± SEM). **p<0.01, ***p<0.001, vs. 1st dose of the compounds (n = 8).

Figure 10

doi: https://doi.org/10.1371/journal.pone.0041909.g010