E22 Primary Afferents| Volume 14, ISSUE 4, SUPPLEMENT , S53, April 2013

Group III mGluR-selective and mGluR8-selective agonists potentiate morphine-induced inhibition of sensitized peripheral nociceptors

      Opioids such as morphine are often used to treat acute and chronic pain. However, they cause significant side effects when taken in high doses or for long periods of time. Current studies aim to establish receptor groups and agonists that might potentiate analgesic efficacy of opioids, allowing treatment with lower doses in order to minimize side effects. One receptor family of interest is the metabotropic glutamate receptors (mGluRs). Current literature indicates that intrathecal and systemic applications of Group III agonists potentiate morphine analgesia. We have previously demonstrated that peripheral administration of the Group III-selective agonist L-AP-4 synergistically potentiates morphine anti-hyperalgesia. In this study, we employed the in vitro skin-nerve preparation to determine if the combination decreases sensitization at the single fiber level. Fibers were sensitized to heat via application of inflammatory soup and morphine, L-AP-4, or a Group III mGluR8-selective agonist (DCPG) was applied. Dose response curves for each drug were used to identify individual IC50s and to determine combination doses of morphine plus either L-AP-4 or DCPG. Further study will involve applying combinations and assessing responses to thermal stimuli to determine if Group III agonists potentiate morphine at the single fiber level. We also examined the anatomical basis of potentiation by double-labeling dorsal root ganglion (DRG) cells for Group III mGluR8 and the mu opioid receptor (μOR). Thus far, data indicate that the receptors are co-localized in 41% of nociceptors. This will be confirmed via triple-labeling DRG cells for mGluR8, μOR, and a nociceptor marker (TRPV1). Co-expression of mGluR8 and μOR on nociceptors suggests that potentiation occurs via an intracellular mechanism. Overall, we expect that peripheral Group III mGluR activation will potentiate morphine-induced inhibition of inflamed peripheral fibers via modulation of an intracellular pathway. Funding: NIH F30DA03229801 to ALB; NS027910/DA027460 to SMC.