Abstract
Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we use in vivo optogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase IIα (CaMKIIα)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.
Highlights
Pain is comprised of both sensory-discriminative and affective-motivational components, which have distinct roles in the pain experience and can often modulate one another
Post hoc analysis revealed that optogenetic activation (ChR2) of glutamatergic neurons in the anterior cingulate cortex (ACC) significantly reduced (p < 0.05 or 0.01) formalin-evoked nociceptive behavior in male rats compared to controls at time bins 9 and 11 of the formalin trial (Figure 3A)
In female rats, optogenetic activation (ChR2) of glutamatergic neurons significantly increased (p < 0.05 or 0.01) formalin-evoked nociceptive behavior compared to controls at time bins 7–9 (Figure 3B)
Summary
Pain is comprised of both sensory-discriminative and affective-motivational components, which have distinct roles in the pain experience and can often modulate one another. It has been found that lesion of the ACC reduces both formalin-induced conditioned place aversion (F-CPA) and visceral pain-induced CPA, pre-clinical behavioral paradigms used to investigate the affective component of pain, without affecting nociceptive responding (Johansen et al, 2001; Gao et al, 2004; Yan et al, 2012). Glutamatergic transmission and the expression of glutamatergic receptors in the ACC are increased in animal models of pain (Xu et al, 2008; Chen et al, 2014; Li W. et al, 2014; Yi et al, 2014; Hubbard et al, 2015; Liu et al, 2015), as well as clinically in patients with chronic pain conditions (Kameda et al, 2017; Lv et al, 2018). Glutamatergic transmission within the ACC plays an important role in CPA
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