Endogenous opioid antagonism in physiological experimental pain models: a systematic review

Mads U Werner, Manuel P Pereira, Lars Peter H Andersen, Jørgen B Dahl, Mads U Werner, Manuel P Pereira, Lars Peter H Andersen, Jørgen B Dahl

Abstract

Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using 'inhibitory' or 'sensitizing', physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized 'inhibitory' test paradigms (ITP) and 38 studies utilized 'sensitizing' test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), 'pain' models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 'pain' model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. The search algorithm according to…
Fig 1. The search algorithm according to the PRISMA-requirements [126].
Fig 2. Schematic illustration of the ʻinhibitoryʼ…
Fig 2. Schematic illustration of the ʻinhibitoryʼ test paradigms (ITP, upper panel) and the ʻsensitizingʼ test paradigms (STP, lower panel).
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 [31] and application of capsaicin [35,36], 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.

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Source: PubMed

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