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.
Highlights
Pain is an experience that has somatosensory, affective, motivational and cognitive characteristics (Melzack and Casey, 1968), involves different brain regions and encompasses diverse neurochemical mechanisms (Bushnell et al, 2013)
The present study evaluates the effect of CBD, injected either systemically or locally into the rostral ACC (rACC), on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain
The present study has shown for the first time that CBD injected either systemically or into the rACC induces a long-lasting antiallodynic effect with a bell-shaped dose-response curve in a rat model of incision pain
Summary
Pain is an experience that has somatosensory, affective, motivational and cognitive characteristics (Melzack and Casey, 1968), involves different brain regions and encompasses diverse neurochemical mechanisms (Bushnell et al, 2013). These mechanisms include multiple ascending spinal pathways to the brain, and this afferent circuitry is controlled by “top-down processing”. The anterior cingulate cortex (ACC) is a crucial component in an interconnected network of brain regions involved in pain perception, stress, anxiety, and reward (Etkin et al, 2011; Navratilova and Porreca, 2014; Zhang et al, 2017). The rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. We explored whether CBD underlies the reward of pain relief after systemic or rACC injection
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