title: Ultralow dose fentanyl prevents development of chronic neuropathic pain in rats.
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 (κ-opioid) also affect post-nerve-injury neuropathy (a rat model of chronic constriction nerve injury [CCI]).
  
  
  METHODS
  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 κ-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.
authors.affiliation: Department of Anesthesiology, University of Kentucky, Lexington, KY, USA.
authors.forename: Elzbieta P
authors.initials: EP
authors.lastname: Wala
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Holtman
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sloan
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D059350:Chronic Pain / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D008297:Male; D009437:Neuralgia / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D012737:Sex Factors; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D005283:Fentanyl