HEME-OXYGENASE INHIBITORS: A NOVEL STRATEGY FOR TREATING CHRONIC AND PERSISTENT PAIN
Philbrook, Michael J. P.
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It is well recognized that there is a lack of effective therapies for treating chronic pain. Therefore, development of novel analgesics with minimal side effects and the absence of addiction potential are essential. The present study assessed the effectiveness of a novel class of selective heme oxygenase (HO) inhibitors in models of inflammatory and neuropathic pain in rats. A research collaboration of Dr. Kanji Nakatsu (Pharmacology and Toxicology) and Dr. Walter Szarek (Chemistry) has designed and synthesized a series of azole-based compounds with a range of activity as HO inhibitors. This series has been dubbed as QC-xx. QC-15 selectively inhibits the HO-1 isoform, while QC-10 inhibits both HO-1 and HO-2. Intraplantar injection of 1% formalin produces a biphasic nociceptive response characterized by licking and flinching of the affected hind paw. Intraperitoneal (IP) administration of QC-15 (100μmol/kg) attenuated nociceptive behaviors to formalin, which were not blocked by the opioid receptor antagonist, naloxone (1 mg/kg, IP). Similarly, IP delivery of QC-10 (100μmol/kg) decreased formalin-induced nociceptive behavior. To determine whether the effects of the drug were peripheral or spinally mediated, compounds were delivered either locally or spinally. Intrathecal (IT) administration of QC-15 (0.3 μmol) attenuated pain behavior, whereas local injection into the paw had no effect. The effects of QC-15 were also assessed in a model of neuropathic pain, induced by constriction of the common sciatic nerve using 4 chromic sutures. Mechanical withdrawal thresholds (von Frey filaments) were used to assess mechanical allodynia before and after IP administration of QC-15. Animals treated with the HO-1 inhibitor had significantly higher thresholds (indicating decreased mechanical allodynia) on both day 7 and 14 compared to pre-drug baselines. These observations suggest that HO-1 may also play a role in neuropathic pain. Finally we were able to demonstrate that QC-15 had no effect on motor coordination that would interfere with behavioral testing. Animals treated with the 100μmol/kg dose of QC-15 were able to maintain equal performance as controls treated with saline. In conclusion, behavioral results indicate that the inducible form of HO (HO-1) may play an important role in persistent and chronic pain states.