Abstract
Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.
Highlights
Pain is a fundamental and evolutionarily conserved cognitive construct that is behaviourally prioritised by organisms to protect themselves from harm and facilitate survival
We have shown that two parallel pathways are implicated in driving brainstem activity related to attentional analgesia (Brooks et al, 2017; Oliva et al, 2021b)
125 point) reduction in pain score (P=0.049) confirming it as being smaller than that seen in the presence of placebo or reboxetine. This effect was specific to attentional analgesia as naltrexone had no effect on the calibrated temperature for the high thermal stimulus or the speed of character presentation for the rapid serial visual presentation (RSVP) task (Figure 2 Supplementary Figure 3). Behaviourally these findings indicate that the attentional analgesic effect is robust, reproducible between and across subjects and that it involves an opioidergic mechanism
Summary
Pain is a fundamental and evolutionarily conserved cognitive construct that is behaviourally prioritised by organisms to protect themselves from harm and facilitate survival. There are well recognised top-down influences on pain that can either suppress (e.g. placebo (Wager and Atlas, 2015) or task engagement (Bussing et al, 2010)) or amplify (e.g. catastrophising (Gracely et al, 2004), hypervigilance (Crombez et al, 2004) or nocebo (Benedetti and Piedimonte, 2019)) its expression. A simple shift in attention away from a noxious stimulus can cause a decrease in pain perception – a phenomenon known as attentional analgesia This effect can be considered to be a mechanism to enable focus, allowing prioritisation of task performance over pain interruption (Eccleston and Crombez, 1999; Erpelding and Davis, 2013). This phenomenon is reliably demonstrable in a laboratory setting (Miron et al, 1989) and a network of cortical and brainstem structures have been implicated in attentional analgesia (Bantick et al, 2002; Brooks et al, 2017; Bushnell et al, 2013; Lorenz et al, 2003; Petrovic et al, 2002; Peyron et al., 2000; Sprenger et al, 2012; Tracey et al, 2002; Valet et al, 2004)
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