Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats, Karina Genaro et al., 2017

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

Karina Genaro, Débora Fabris, Ana L. F. Arantes, Antônio W. Zuardi, José A. S. Crippa and Wiliam A. Prado

Frontiers in Pharmacology, June 2017 | Volume 8 | Article 391

doi : 10.3389/fphar.2017.00391


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 mL) injected into the rACC reduced mechanical allodynia in a dosedependent manner. CBD (5 nmol/0.25 mL) 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 : endocannabinoids, cannabidiol, pain, allodynia, aversion, anterior cingulate cortex



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). ACC neurons connect with several regions important for pain processing, including the prelimbic, infralimbic and insular cortex, medial thalamus, amygdala, nucleus accumbens, and hippocampus (Strassels, 2006; Tracey and Mantyh, 2007; Vogt and Vogt, 2009; Neugebauer, 2015). The role of the rostral ACC (rACC) in the experience of pain has been confirmed in rodents (Johansen et al., 2001) and primates (reviewed in Shackman et al., 2011). Lesions of the ACC and cingulum bundle suppress emotional reactions of human patients to persistent pain (Foltz and White, 1962, 1968).

Considering the multidimensionality of pain, research within the last two decades has sought alternative treatment approaches, but the number of new drugs that have reached the stage of clinical trials has been still small (MacPherson, 2000). The endocannabinoid (eCB) signaling system regulates a broad spectrum of physiologic processes and has attracted considerable attention as a potential pharmaceutical target for modulating pain perception, emotional state, reward behaviors, learning and memory (Pacher et al., 2006; Bambico et al., 2007, 2009; Ahn et al., 2008; Di Marzo, 2008; Palazzo et al., 2010; Luongo et al., 2017).

Multiple biochemical pathways may participate in eCB formation (Di Marzo et al., 1994). Anandamide and 2- arachidonoylglycerol (2-AG) are the best-studied eCB isolated so far (Devane et al., 1992; Mechoulam et al., 1995) and produce their physiological effects by activating the cannabinoid CB1 and CB2 receptors (Matsuda et al., 1992; Munro et al., 1993; Kendall and Yudowski, 2017). These receptors have a characteristic distribution in the nervous system which is particularly enriched in cortex, hippocampus and amygdala, a distribution that corresponds to the most prominent behavioral effects of cannabinoids (Mackie, 2008). Although the eCB system plays an important role in nerve signal transduction at the central and peripheral levels, the lifespan of extracellular eCB is limited by a rapid and selective process of cellular uptake, which is accompanied by the actions of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for anandamide and 2-AG, respectively (Piomelli, 2005).

For this reason, eCB appear to play a limited role, which might explain the difficulty of detecting effects of eCB in behavioral and neurochemical studies (Piomelli, 2003). Phytocannabinoids found in Cannabis sativa, such as 19-tetrahydrocannabinol (THC) and cannabidiol (CBD) and synthetic cannabinoids – metabolically and chemically more stables – and inhibitors of eCB inactivation have been shown to enhance the action of eCB in reducing pain, inflammation, anxiety and depression in rodents with negligible changes in motility and behavior, as observed with direct CB1 agonists (Piomelli et al., 2006; Russo et al., 2007; Ahn et al., 2008; Petrosino and Di Marzo, 2010; Jensen et al., 2015; Kramer, 2015). Inhibitor of FAAH induces antidepressant-like effects in rodents (Gobbi et al., 2005) and genetic deletion of FAAH in mice confers resistance to anxiety-like and depression-like behavioral responses (Bambico et al., 2012). Results from preclinical and clinical studies suggest that CBD is an effective, safe, and welltolerated drug (Russo and Guy, 2006). Although CBD is a negative allosteric modulator and displays low affinity for CB1 and CB2 receptors, it enhances eCB signaling in rodents through an inhibitory action on the mechanisms of eCB inactivation (i.e., the transporter and the FAAH enzyme) (Bisogno et al., 2001; Leweke et al., 2012). CBD has been considered a promising strategy against inflammatory diseases (Carrier et al., 2006) and neuropathic pain (Costa et al., 2007). However, the action of CBD on pain-induced affective-motivational changes has not been described. Notably, persistent pain conditions are often accompanied by emotional and cognitive disorders. These dysfunctional or maladaptive changes in aversive/motivational circuits likely contribute to the challenges of treating persistent pain.

The experimental approaches and methods used to measure the affective dimension of pain are still poor. A successful attempt has been made to assess pain as the opposite of pleasure, and its relief often promotes a positive emotional state that has been described as a reward (Fields, 1999; Leknes et al., 2008). Relief of pain aversiveness has been taken as a negative reinforcement that can be experimentally assessed by a conditioned place preference (CPP) paradigm (King et al., 2009; Navratilova et al., 2013, 2015). A deeper understanding of the neural basis of nociception and its aversive component could not only broaden our view on pain but also open new approaches to the management of acute and persistent pain states. The present study therefore evaluates the effect 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.