Cortico-spinal coupling along descending pain system differentiates between opioid and saline treatment in healthy participants

Opioids are potent analgesic drugs with widespread cortical, subcortical and spinal targets. In particular, the central pain system comprising ascending and descending pain pathways has high opioid receptor densities and is thus crucial for opioid analgesia. Here, we investigated effects of the opioid remifentanil in a large sample (n=78) of healthy male participants using combined cortico-spinal fMRI. This approach offers the possibility to measure BOLD responses simultaneously in the brain and spinal cord allowing us to investigate the role of cortico-spinal coupling in opioid analgesia. Our data show that opioids altered activity in regions involved in pain processing such as somatosensory regions including the spinal cord and pain modulation such as prefrontal regions. Moreover, coupling strength along the descending pain system, i.e. between the medial prefrontal cortex, periaqueductal gray and spinal cord was stronger in participants who reported stronger analgesia during opioid treatment while the reversed pattern was observed in the control group. These results indicate that coupling along the descending pain pathway is a potential mechanism of opioid analgesia and can differentiate between opioid analgesia and unspecific reductions in pain such as habituation.