Pharmacology/Drug Development

Opioids are highly effective analgesics, however their therapeutic use is limited by adverse effects that include respiratory depression, dependence, and tolerance. Inflammation has been implicated as a significant driver for the development of tolerance to opioids. Recent studies show that chronic morphine in mice results in gut microbial dysbiosis and inflammation in the colon. In the present study we examined whether colonic inflammation results in tolerance to the antinociceptive effects of morphine. Colonic inflammation was induced in mice by intrarectal administration of 2,4,6-trinitro-benzene sulfonic acid (TNBS). The development of antinociceptive tolerance was determined by warm-water tail-immersion assay in mice implanted with 25 mg, 50 mg or 75 mg morphine pellet. Colonic inflammation significantly enhanced the rate at which tolerance developed in each cohort of chronic morphine treated mice. At the lowest dose of morphine pellet (25 mg), antinociceptive tolerance only developed in the presence of colonic inflammation; whereas, in 50 mg and 75 mg pelleted mice, tolerance developed faster in the inflamed animals than the non-inflamed mice. The enhanced antinociceptive tolerance was attenuated with daily administration of peripheral opioid receptor antagonist, 6β-N-heterocyclic substituted naltrexamine derivative (NAP), irrespective of colonic inflammation. Collectively, these findings show that the rate of tolerance to morphine antinociception is exaggerated in the presence of colonic inflammation and tolerance is prevented by a peripheral mu-opioid receptor antagonist. These studies suggest a peripheral component to the development of antinociceptive tolerance to opioids. Furthermore, peripherally selective opioid antagonists may be useful adjuncts in opioid based pain management. SIGNIFICANCE STATEMENT: Our study supports the notion that inflammation influences the development of antinociceptive tolerance to chronic morphine exposure. We found that as the dose of morphine increased in the presence of colonic inflammation, the more tolerant the mice became to the antinociceptive effects of morphine. We also found that treatment with a peripheral opioid receptor antagonist prevented morphine antinociceptive tolerance. By increasing opioid intake during an inflammatory state would result in decreased analgesia and enhanced analgesic tolerance, which puts patients with inflammatory bowel diseases, inflammatory joint diseases, and sickle cell anemia at risk for a heavy opioid use.

Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis.

Tolerance to the antinociceptive effect of mu-opioid receptor (MOPr) agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co-administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by assessment of cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross-tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low-doses of morphine and fentanyl. In conclusion, cross-tolerance does not develop between morphine and fentanyl within the vlPAG. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance following morphine and fentanyl binding to the MOPr. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to reduce opioid tolerance and other side effects. Perspective: This preclinical study shows that there is a reduction in cross tolerance between morphine and fentanyl within the periaqueductal gray which is key brain region in opioid antinociception and tolerance.

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely due to the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb, or systemic delivery of an anti-P2X4 bi-specific mAb with enhanced blood-spinal cord barrier permeability, produced long lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.

The adverse effects of opioids are largely mediated by central μ-opioid receptorsCentral μ- and δ-opioid receptors synergistically provide analgesia WHAT THIS ARTICLE TELLS US THAT IS NEW: The administration of a selective δ-opioid agonist, oxymorphindole, and a peripherally-restricted μ-agonist, loperamide, provided synergistic analgesia in a mouse inflammatory pain modelThe use of combinations of peripherally-restricted opioid ligands may provide analgesia with reduced side effects when compared with centrally acting opioids BACKGROUND:: The long-term use of opioids for analgesia carries significant risk for tolerance, addiction, and diversion. These adverse effects are largely mediated by μ-opioid receptors in the central nervous system. Based on the authors' previous observation that morphine and δ-opioid receptor agonists synergize in spinal cord in a protein kinase Cε-dependent manner, they predicted that this μ-opioid receptor-δ-opioid receptor synergy would take place in the central terminals of nociceptive afferent fibers and generalize to their peripheral terminals. Therefore, the authors hypothesized that loperamide, a highly efficacious μ-opioid receptor agonist that is excluded from the central nervous system, and oxymorphindole, a δ-opioid receptor agonist that was shown to synergize with morphine spinally, would synergistically reverse complete Freund's adjuvant-induced hyperalgesia.