The rostral ventral medulla (RVM) is implicated in the descending modulation of pain. The RVM is enriched in mu-, delta- and kappa opioid receptors. Systemic opioid agonist administration of infusion of these agents directly into the RVM produces antinociception. The selective blockade of opioid receptors in the RVM attenuates the analgesic effect of systemically administered opiates indicating that activation of opioid receptors in this brain region is both sufficient and necessary for the production of antinociception.? ? Several studies have shown that thermal analgesic produced by supraspinal infusion of mu or delta opioid receptor agonists is potentiated during persistent inflammation. Whether this potentiation extends to other stimulus modalities (e.g. mechanical stimuli) or to kappa opioid receptor agonists is unknown. To examine these issues, we used the Complete Freund's adjuvant(CFA)model of peripheral inflammation. Intraplantar injection of CFA to rodents produces inflammation, allodynia and hyperalgesia of the injected paw. Antinociception produced by RVM infusion of the kappa opioid receptor agonist, U69593, and the mu opioid receptor agonist, DAMGO, was tested 4hrs - 2 weeks after injection by assessing thermal paw withdrawal latencies and mechanical thresholds of the inflammed and non-inflammed hindlimb. Withdrawal latencies and mechanical thresholds of the inflamed paw were reduced for at least 2 weeks after the induction of inflammation consistent with the development of thermal hyperalgesia and mechanical allodynia. Infusion of either U69593 or DAMGO increased withdrawal latencies of both hindlimbs. A bilateral enhancement of the response to agonists was observed 2 weeks relative to 4h post-CFA injection. Agonist infusion elevated mechanical thresholds of the inflamed and non-inflamed paws. The magnitude of the DAMGO effect was greater 2 weeks after the induction of inflammation whereas the effects of U69593 increased progressively as a function of the duration of inflammation. These data demonstrate that RVM infusion of mu- or kappa agonists attenuates thermal and tactile allodynia and that these effects increase during prolonged inflammation. The augmented response of the non-inflamed paw to agonists suggests that inflammation induces centrally-mediated neuroplastic changes in endogenous opioid systems which enhance antinociception. ? ? In a series of studies we have investigated whether the activity of endogenous kappa-opioid receptor systems is altered in response to inflammatory pain and whether this adaptation serves an essential function in limiting allodynia and hyperalgesia. Inflammation was induced by intraplantar injection of CFA into one hindpaw. Mechanical and thermal thresholds were determined using the Von Frey and radiant heat tests, respectively. Deletion of the gene encoding the kappa opioid receptor or systemic administration of the long-acting kappa opioid receptor antagonist, norbinaltorphimine (norBNI) significantly exacerbated mechanical and thermal hypersensitivity of the inflamed paw. Thermal and mechanical thresholds of the non-inflamed, contralateral hindpaw were unaffected by CFA treatment. However, gene deletion as well as norBNI treatment resulted in mechanical hypersensitivity of the non-inflamed paw. Similar results were obtained when norBNI was administered intrathecally or into the RVM in rats. These data demonstrate a previously unrecognized role of endogenous kappa opioid receptor systems in inhibiting hyperalgesia during inflammation. Furthermore, they demonstrate that decreased activity of this opioid system in either the spinal cord or RVM not only enhances mechanical and thermal hyperalgesia of the inflamed limb but also leads to an unmasking of mechanical hyperalgesia at a site remote from inflammation.? ? GABAergic and glutamatergic signaling is implicated in RVM-mediated opiate antinociception. Infusion of GABA receptor antagonists into the RVM produces analgesia. Infusion of glutamate into this region produces similar effects. Analgesia produced by systemic morphine administration can be prevented by RVM administration of GABA-A receptor agonists or excitatory amino acid receptor antagonists suggesting an involvement of these amino acid neurotransmitters in mu-opioid receptor mediated analgesia. However, studies directly testing this hypothesis in the behaving animal are lacking. We used in vivo microdialysis to investigate this issue. Local perfusion of the selective mu-opioid receptor agonist, DAMGO, produced a concentration-dependent decrease of GABA release in the RVM. Only concentrations of DAMGO that decreased GABA levels increased thermal withdrawal thresholds. DAMGO did not alter glutamate concentrations in dialysates. Addition of KCl (60 mM) was also without effect. Since rapid, transporter-mediated uptake may mask detection of changes in glutamate release, the selective excitatory amino acid transporter inhibitor pyrrolidine-2,4-dicarboxylic acid (tPDC) was added to the perfusion medium for subsequent studies. tPDC increased glutamate concentrations, confirming transport inhibition. KCl increased microdialysate levels of gluatame in the presence of tPDC demonstrating that transport inhibition permits detection of depolarization-evoked glutamate release. In tthe presence of tPDC, DAMGO increased glutamate levels in a concentration-dependent manner. These data provide the first direct demonstration that mu opioid receptor activation decreases GABA and increases glutamate release in the RVM. We hypothesize that the opposing effects of mu-opioid receptor activation on glutamate and GABA transmission contribute to opiate antinociception.? ? We have initiated studies to determine whether expression of a novel family of proteins that facilitate clustering of the AMPA type glutamate receptor is altered in response to nerve injury and inflammation and whether manipulations that affect protein expression can modulate nociception. Using the spared nerve injury model in rodents, we have found that deletion of the gene encoding this protein prevents nerve injury evoked mechanical allodynia and hyperalgesia. Silencing of the gene encoding this protein in the RVM not only prevents the development of injury-evoked allodynia and hyperalgesia but reverses their expression. Deletion of this protein significantly affects CFA- and formalin evoked nociceptive responses as well as the mechanical allodynia resulting from retroviral therapy-associated peripheral neuropathy. These findings suggest that proteins that facilitate AMPA transmission may represent a novel target for the development of effective therapeutics for the treatment of chronic pain.
| Schepers, Raf Jan-Filip; Mahoney, Janet Lynn; Shippenberg, Toni Shaun (2008) Inflammation-induced changes in rostral ventromedial medulla mu and kappa opioid receptor mediated antinociception. Pain 136:320-30 |
| Schepers, Raf Jan-Filip; Mahoney, Janet Lynn; Zapata, Agustin et al. (2008) The effects of local perfusion of DAMGO on extracellular GABA and glutamate concentrations in the rostral ventromedial medulla. J Neurochem 104:806-17 |
| Schepers, R J; Mahoney, Janet Lynn; Gehrke, Brenda Jean et al. (2008) Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation. Pain 138:423-39 |
