Endogenous Opioid Activity in the Anterior Cingulate Cortex Is Required for Relief of Pain

Abstract

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an ␣ 2 -adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

“…We found only subtle modifications of structural scaffolding (Fig. 4), contrasting the rich remodeling of FC and consistent with the neuromodulatory nature of the single missing gene (13,34,35).…”

Brain Circuits Encoding Reward from Pain Relief

“…LaGraize et al, have demonstrated that in neuropathic rats, microinjection of morphine into the ACC produced a selective decrease of affective/motivational aspects of pain with no alteration of mechanical paw withdrawal threshold (76). Similarly, we have shown that ACC morphine produced CPP in rats with post-surgical and neuropathic pain but not in uninjured animals (77) (Fig. 2A).…”

“…Opioid blockade in the ACC had no effect on behavioral thresholds to evoked stimuli. Thus, endogenous opioidergic circuits within the ACC are both necessary and sufficient for reward from pain relief (77). Because activation of opioid receptors in the ACC has no effect on motivated behavior in uninjured rats, it is likely that increased ACC opioid activity in the setting of ongoing pain produces reward by alleviating aversiveness.…”

“…Thus, indirect methods of using blockade of opioid receptors in the ACC have been employed. In injured animals, microinjection of opioid receptor antagonists in the ACC prevented motivated behavior for pain relief (CPP) as well as relief-induced tonic dopamine release in the NAc (77). This study is the first demonstration that endogenous opioid signaling in the ACC is required for pain relief-motivated behavior.…”

Neuroimaging mechanisms in pain: from discovery to translation

“…125 Animal work supports this view and shows that for nonopioidbased treatments, functional rostral anterior cingulate cortex endogenous opioid activity is required to elicit nucleus accumbens dopamine release and subsequent analgesia from neuropathic pain. 87 It is notable that pain intensity ratings in the Vachon-Presseau et al study did not significantly worsen over the 3 years and that only a reduction in pain intensity of .20% was required to be considered as "recovered." Therefore, one might speculate about the interrelationship between lack of effective analgesia and the maintenance/or development of chronic pain, as defined here.…”