*3.4. The Nociceptive Sensitivity Investigation*

The oral administration of DEX resulted in a significant (\*\* *p* < 0.01) lengthening of the paws' latency time response, an effect that was prolonged for four hours (\* *p* < 0.05), then progressively reduced after about 10 h (\* *p* < 0.05) in the hot plate test. Its maximum possible antinociceptive effect was achieved at 60 min (%MPE = 56.6 ± 8.7%) in this experimental somatic pain model in rats (Figure 6).

The treatment with DEX produced a substantial and rapid analgesic effect, even after 15 min, which was manifested for four hours. After this period, the effect progressively decreased, reaching intensity comparable with that observed in the group treated with distilled water in the hot plate. The highest intensity of the antinociceptive activity (56.6 ± 8.7%) was noted 60 min after the substance administration in this somatic pain model in rats.

The use of nano-DEX was correlated with an increase in the latency time reactivity to thermal noxious stimulation, which began after 90 min, and lasted for about 10 h (Figure 2). Its maximum possible antinociceptive effect was achieved at 6 h (%MPE = 49.4 ± 5.3%) in the experiment (Figure 7). *Polymers* **2021**, *13*, x FOR PEER REVIEW 10 of 14

**Figure 6.** The effects of nano-DEX in the hot plate test. Each point is the mean ± S.D. of the latency. \* *p* < 0.05, \*\* *p*< 0.01 compared to control. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen. **Figure 6.** The effects of nano-DEX in the hot plate test. Each point is the mean ± S.D. of the latency. \* *p* < 0.05, \*\* *p* < 0.01 compared to control. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen. **Figure 6.** The effects of nano-DEX in the hot plate test. Each point is the mean ± S.D. of the latency. \* *p* < 0.05, \*\* *p*< 0.01

compared to control. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen.

**Figure 7.** The percentage maximum possible antinociceptive effect (%MPE) of nano-DEX in the hot plate test. Each point is the mean ± S.D. for six rats. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen. **Figure 7.** The percentage maximum possible antinociceptive effect (%MPE) of nano-DEX in the hot plate test. Each point is the mean ± S.D. for six rats. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen. **Figure 7.** The percentage maximum possible antinociceptive effect (%MPE) of nano-DEX in the hot plate test. Each point is the mean ± S.D. for six rats. DW: distilled water; DEX: dexketoprofen; nano-DEX: liposomes containing dexketoprofen.

The treatment with chitosan-coated liposomes entrapping DEX was accompanied by a strong analgesic effect, which began after 120 min and persisted for up to 8 h, being the most intense (with a maximum analgesic effect of 51.7 ± 10.5%) at 6 h in this experimental somatic pain model. After this moment of determination, the effects of nano-DEX were The treatment with chitosan-coated liposomes entrapping DEX was accompanied by a strong analgesic effect, which began after 120 min and persisted for up to 8 h, being the most intense (with a maximum analgesic effect of 51.7 ± 10.5%) at 6 h in this experimental somatic pain model. After this moment of determination, the effects of nano-DEX were comparable with those noted for free DEX, as well as for distilled water in the hot plate test in rats. The treatment with chitosan-coated liposomes entrapping DEX was accompanied by a strong analgesic effect, which began after 120 min and persisted for up to 8 h, being the most intense (with a maximum analgesic effect of 51.7 ± 10.5%) at 6 h in this experimental somatic pain model. After this moment of determination, the effects of nano-DEX were comparable with those noted for free DEX, as well as for distilled water in the hot plate test in rats.

comparable with those noted for free DEX, as well as for distilled water in the hot plate

Data in the literature show that each of the non-steroidal anti-inflammatory drug-loaded nano-formulations was demonstrated to be beneficial in correct pain management, leading to a safer and more precise medication. Furthermore, the prolonged

agement, leading to a safer and more precise medication. Furthermore, the prolonged

test in rats.

**4. Discussion**

**4. Discussion**
