Schematic illustration of the ʻinhibitoryʼ test paradigms (ITP, upper panel) and the ʻsensitizingʼ test paradigms (STP, lower panel).

<p>The ITP-studies employed an inhibitory conditioning stimulus with evaluation of the associated change in the applied test-stimulus (△test-stimulus). The objective of the ITP-studies was to examine the effect of mu-opioid-receptor (MOR) antagonist on the magnitude of the △test-stimulus, indicating an activation of the endogenous opioid system (EOS) responsible for the conditioning response leading to antinociception/hypoalgesia (the central rectangle [Opioid-dependent mechanism?] indicates a hypothetical augmentation of the conditioning response by the EOS). The STP-studies (lower panel) employed a pain stimulus leading to quantifiable ʻsensitizingʼ CNS-responses, e.g., changes in behavioral measures (hyperalgesia, pain ratings, thresholds, tolerance), nociceptive reflexes, neuroimaging or neuroendocrine variables. In a number of studies a sensitizing conditioning stimulus was applied, e.g., a burn injury [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref031" target="_blank">31</a>] and application of capsaicin [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref035" target="_blank">35</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref036" target="_blank">36</a>], enhancing the nociceptive responses. The objective of the STP-studies was to examine the effect of MOR-antagonist on the magnitude of elicited responses, indirectly either supporting or contradicting an effect mediated by the EOS (the central rectangle [Opioid-dependent mechanism?] indicates a hypothetical attenuation of the response by the EOS). FM Peripheral Conditioning = non-noxious Frequency Modulated Peripheral Conditioning; rTMS = repetitive Transcranial Magnetic Stimulation.