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Ultralow dose fentanyl prevents development of chronic neuropathic pain in rats

Elzbieta P. Wala, PhD, Joseph R. Holtman Jr, MD, PhD, Paul A. Sloan, MD

Abstract


Background: Opioids may cause progressive enhancement of pain sensitivity (opioid-induced hyperalgesia [OIH]) and thus, exacerbate existing pain. Animal studies also demonstrate paradoxical OIH with an ultralow dose (ULD, subanalgesic) of opioid; eg, the µ-opioid, morphine. Repeated administration of ULD-morphine resulted in tolerance to ULD-OIH. Prior exposure to ULD-morphine prolonged subsequent morphine antinociception in intact rats (delay of tolerance) and blocked neuropathic pain in nerve-injured rats (no hyperalgesia). Hence, pre-emptive desensitization of the excitatory function of opioid receptors may reduce further activation of a pain facilitatory system exerted by opioid or nerve injury. Objective: We determined if ULD-fentanyl (µ-opioid) and U50488H (?-opioid) also affect post-nerve-injury neuropathy (a rat model of chronic constriction nerve injury [CCI]). Design: Fentanyl (0.5-500 ng/kg) was administered acutely in noninjured rats. Chronic fentanyl (5 ng/kg/day) was initiated either immediately after CCI (day 1-28) or when neuropathy was established (day 7-14) in nerve-injured rats. U50488H (25 µg/kg/day) was given on day 1-28 post-CCI. Saline served as control. Responsiveness was assessed using tail-flick and paw-pressure tests, respectively, in intact and CCI Sprague-Dawley rats of both sexes. Results: ULD-fentanyl evoked pain sensitization in noninjured rats. ULD-OIH was related to dose (inversely), gender (female > male), and was reversed by ketamine. Neuropathy developed after CCI in control (saline) rats. This was not observed in rats of either sex exposed to ULD-fentanyl on day 1-28 post-CCI. Rats treated with ULD-fentanyl from day 7 after CCI exhibited hyperalgesia similar to control rats. U50488H did not block post-CCI neuropathy (regardless of gender). Conclusions: Pre-emptive use of ULD µ-opioid (not ?-opiod) blocked initiation (not maintenance) of neuropathic pain after CCI in rats. These data may suggest a novel treatment approach in situations when the potential development of neuropathy can be anticipated. Keywords: neuropathy, opioid-induced hyperalgesia, µ-opioid agonist, ?-opioid agonist, subanalgesic dose, neuropathy initiation, neuropathy maintenance

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DOI: https://doi.org/10.5055/jom.2013.0150

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