Repeated ketamine administration induces cross-tolerance to sodium salicylate but not to morphine in male rats

Abstract

Cross-tolerance profiles provide critical insights into shared neurobiological substrates among analgesics. This study evaluated whether repeated sub-anesthetic ketamine administration induces cross-tolerance to morphine or sodium salicylate. Thirty-six adult- male Wistar rats (180–200 g, n = 6/group) received either normal saline or ketamine (10 mg/kg, i.p.) once daily for 8 consecutive days. Antinociceptive thresholds were assessed daily using the hot-plate test (52 ± 0.5 °C) at 45 min post-injection and expressed as the percentage of maximum possible effect (MPE%). On day 9, acute cross-tolerance challenges were conducted using morphine (10 mg/kg, i.p.) or sodium salicylate (300 mg/kg, i.p.). Serum malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured on day 8 to evaluate systemic oxidative status. Repeated ketamine administration produced a progressive decline in MPE%, demonstrating marked antinociceptive tolerance by day 8. On day 9, morphine maintained full antinociceptive efficacy in ketamine-pretreated rats, indicating no cross-tolerance. Conversely, sodium salicylate-induced antinociception was significantly blunted, confirming cross-tolerance. Biochemically, ketamine pre-treatment did not elevate serum MDA and preserved SOD activity substantially better than morphine. In conclusion, repeated sub-anesthetic ketamine administration induces antinociceptive tolerance and selective cross-tolerance to sodium salicylate, while sparing morphine responsiveness. These behavioral adaptations parallel a favorable redox balance, highlighting distinct pharmacodynamic mechanisms governing ketamine interactions with opioid versus non-opioid regimens.