Previous studies show that the endogenous opioid system has an important role in the pain control system. In recent years, it has also been suggested that epigenetic modifications, such as acetylations, may affect pain sensitivity. Inhibition of histone deacetylases (HDACs) might lead to analgesia through prolonged activation of the NF-κB pathway, followed by an upregulation of mGlu2/3 receptors. Activation of mGlu2/3 receptors on the primary afferent neurons is believed to have an antinociceptive effect through inhibition of spinal glutamate release, and consequently on the spinal and supraspinal nociceptive transmission.To investigate the activation of the supraspinal opioid system to noxious peripheral stimuli, spinal long-term potentiation (LTP) was induced by high frequency stimulation (HFS) conditioning applied to the sciatic nerve. Opioid tracer binding, i.e. opioid receptor (OR) availability, was measured prior and subsequent to the HFS conditioning by positron emission tomography (PET) imaging with the OR agonist radioligand [18F]PEO. To further investigate the potential effect of HDAC inhibition on the supraspinal opioid system, a group of animals were pretreated with the HDAC inhibitor MS-275 (3 mg/kg s.c.) once every 24 h for 5 consecutive days prior to the PET scans. RT-qPCR was applied to investigate changes in gene expression encoding the OR-μ, OR-κ, pre-proenkephalin and cholecystokinin B receptors in the ipsilateral hippocampus, due to their potential role regarding the opioidergic system.The present study demonstrated that induction of spinal LTP by HFS conditioning was associated with a reduced opioid tracer binding in the ipsilateral primary somatosensory cortex, visual cortex, and hippocampus. The observed decrease in opioid tracer binding is most likely explained by an increase in the endogenous opioid peptide release. Similar observation was done in the somatosensory cortex of the MS-275 pretreated animals. However, the reduction in opioid tracer binding was less pronounced compared with the untreated animals. Notably, no significant changes in opioid tracer binding were observed in the other parts of the brain, i.e. visual cortex and hippocampus, in the pretreated animals. Hence, an overall tendency of reduced activation of the endogenous opioid system was observed in the MS-275 pretreated animals compared with the untreated animals. The gene expression analyses did not show any significant changes in the expression of the target genes after HFS conditioning.In conclusion, the present findings suggest that a peripheral noxious stimulation that induces spinal LTP may activate the supraspinal OR system, especially in the hippocampus. This activation seems to be less pronounced after inhibition of HDACs. This may imply that inhibition of HDACs attenuate the activation of the OR system upon induction of LTP.