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. 2017 Jun 21;8:391.
doi: 10.3389/fphar.2017.00391. eCollection 2017.

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

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Free PMC article

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

Karina Genaro et al. Front Pharmacol. .
Free PMC article

Abstract

Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection. Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness. Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD.

Keywords: allodynia; anterior cingulate cortex; aversion; cannabidiol; endocannabinoids; pain.

Figures

FIGURE 1
FIGURE 1
Reduction of tactile hypersensitivity by Cannabidiol (CBD). (A) Timeline of the protocol for the experiments; (B) The time-course of changes in the withdrawal thresholds (WT) measured in the operated and contralateral hind paws of the rats. Baseline (BL) was measured preoperatively (BL1) and 24 h postoperatively (BL2). Subsequently, the rat groups were treated with vehicle (VEH; n = 6) or CBD 0.3 to 30 mg/kg (n = 7–10), and WT was measured up to 150 min after injection. Arrows 1 and 2 indicate the times of surgery and intraperitoneal injection, respectively. Two-way ANOVA with Dunnett’s test: p < 0.05 compared with vehicle. Data are means ± SEMs.
FIGURE 2
FIGURE 2
Cannabidiol may reduce (low doses) or invert (higher doses) the conditioned place preference (CPP) induced by peripheral nerve block. (A) Time line of the protocol for the experiments, (B) Peripheral nerve block produced significant CPP in incised rats pretreated intraperitoneally (i.p.) with vehicle (VEH; n = 16). CBD (0.3 and 0.5 mg/kg) reduced, and CBD (1 to 3 mg/kg) completely inverted, the CPP induced by peripheral nerve block (n = 9–12). One-way ANOVA with Dunnett’s test. The insert shows the time-course of changes in the WT measured in the operated hind paw of the rats. Arrows 1 and 2 indicate the times of surgery and injection, respectively. In rats with incisions, administration of vehicle and low doses of CBD had no effect on mechanical allodynia and its reversal by peripheral nerve block with lidocaine (LID) injected into the popliteal fossa (p.f.) of the injured limb. SAL, saline. Two-way ANOVA with Dunnett’s test: p < 0.05 compared with vehicle. Data are means ± SEMs.
FIGURE 3
FIGURE 3
Cannabidiol induced significant CPP in incised but not sham rats. (A) Timeline of the protocol for the experiments; (B) CBD (1 mg/kg; n = 13) produced significant CPP only in incised rats. One-way ANOVA with Tukey’s test: p < 0.05 compared with sham-incised groups and vehicle-treated incised group. Data are means ± SEMs. The insert shows that intraperitoneal (i.p.) administration of vehicle (VEH; n = 11) or CBD (1 mg/kg; n = 10) in sham-incised rats as well as vehicle (n = 12) in incised rats produced no significant effect on the WT. Arrows 1 and 2 indicate the times of surgery and injection, respectively.
FIGURE 4
FIGURE 4
Cresyl violet-stained tissue showing the location of the cannula tip in the rostral anterior cingulate cortex. Scale bar = 1 mm.
FIGURE 5
FIGURE 5
Reduction of tactile hypersensitivity by CBD. (A) Timeline of the protocol for the experiments; (B) The time-course of changes in the WT measured in the operated and contralateral hind paws of the rats. Baseline (BL) was measured preoperatively (BL1) and 24 h postoperatively (BL2). Subsequently, vehicle (VEH; n = 6) or CBD (5 to 40 nmol/0.25 μL; n = 7–11) was administered into the rostral anterior cingulate cortex (rACC), and WT was measured up to 120 min after injection. Arrows 1 and 2 indicate the times of surgery and injections into the rACC, respectively. Two-way ANOVA with Dunnett’s test: p < 0.05 compared with vehicle. Data are means ± SEMs. Coronal sections taken from the atlas of Paxinos and Watson (2006) showing the locations of the injections of CBD in the rACC are shown in (C) using symbols as in the graph.
FIGURE 6
FIGURE 6
Cannabidiol into the rACC reduces (low doses) or inverts (higher doses) the CPP induced by peripheral nerve block. (A) Timeline of the protocol for the experiments; (B) Peripheral nerve block produced significant preference in incised rats pretreated intra-rACC with vehicle (VEH; n = 13). CBD (5 nmol/0.25 μL; n = 14) reduced, and CBD (40 nmol/0.25 μL; n = 12) inverted completely, the CPP by peripheral nerve block produced by injection of lidocaine (LID) into the popliteal fossa (p.f.). SAL, saline. One-way ANOVA with Dunnett’s test. The insert shows the time-course of changes in the WT measured in the operated hind paw of the rats. In rats with incisions, administration of vehicle and low doses of CBD had no effects on mechanical allodynia. CBD (40 nmol/0.25 μL) reduced mechanical allodynia. Arrows 1 and 2 indicate the times of surgery and injection, respectively. Two-way ANOVA with Dunnett’s comparison: p < 0.05 compared with vehicle. Data are means ± SEM. Coronal sections taken from the atlas of Paxinos and Watson (2006) showing the location of the injections of CBD in the rACC are shown in (C) using symbols as in the insert.
FIGURE 7
FIGURE 7
Cannabidiol injection into the rACC induced significant CPP in incised rats. (A) Timeline of the protocol for the experiments; (B) CBD at 5 nmol/0.25 μL produced significant CPP in incised rats (n = 12) but not in sham-incised rats (n = 10). One-way ANOVA with Dunnett’s comparison: p < 0.05 compared with sham. Data are means ± SEM. The insert shows that CBD injected into the rACC in incised rats produced no significant effect on paw WTs. Arrows 1 and 2 indicate the times of surgery and injection, respectively. Coronal sections taken from the atlas of Paxinos and Watson (2006) showing the location of the injections of CBD in the rACC are shown in (C) using symbols as in the insert.

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