title: Ketorolac prevents recurrent withdrawal induced hyperalgesia but does not inhibit tolerance to spinal morphine in the rat.
abstract: Chronic use of opioid is associated with pro-nociceptive phenomena such as hyperalgesia or tolerance. The interaction between opioid and non-steroidal anti-inflammatory drugs (NSAIDs) with respect to opioid-associated hyperalgesia and tolerance remains largely unknown. This study examines the effect of subcutaneous or intrathecal administration of ketorolac, an NSAID, on recurrent withdrawal induced hyperalgesia and tolerance to spinal morphine in rats. Animals were infused with morphine intrathecally, and daily subcutaneous naloxone was used for recurrent withdrawal purpose. We observed that escape latencies on hot box were decreased in animals subjected to withdrawal, and this decrease was reversed by subcutaneous ketorolac pretreatment. In addition, we observed that recurrent withdrawal did not significantly affect the magnitude of spinal morphine tolerance. Compared to controls, all morphine infused animals showed similar changes in their dose responses to spinal morphine, effective dose 50 values and tolerance ratios; and these changes were not affected by the ketorolac given subcutaneously. The effect of ketorolac on tolerance was further examined by directly delivering ketorolac to the spinal cord, and again we observed similar changes in the daily latency, percentage of area under the curve and percentage of maximal possible effects among groups infused with morphine, regardless of intrathecal ketorolac treatment. Together, our results demonstrate that recurrent withdrawal is associated with hyperalgesia but this has no effect on the tolerance development; ketorolac protects against recurrent withdrawal induced hyperalgesia without significantly altering spinal morphine tolerance.
authors.affiliation: Department of Anesthesiology, Pain Management Center, Baystate Medical Center, Tufts University, 3400 Main Street, Springfield, MA 01199, USA. Stuart.dunbar@bhs.org
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Dunbar
authors.forename: Ivan
authors.initials: I
authors.lastname: Karamian
authors.forename: Jiahui
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D007278:Injections, Spinal; D020910:Ketorolac / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000378:metabolism / Q000503:physiopathology; D009270:Naloxone / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000009:adverse effects; D010147:Pain Measurement / Q000187:drug effects; D010148:Intractable Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D020910:Ketorolac