title: The local peripheral antihyperalgesic effect of levetiracetam and its mechanism of action in an inflammatory pain model.
abstract: BACKGROUND
  We have recently shown that levetiracetam, administered systemically, exerts an antihyperalgesic effect in a rat inflammatory pain model. In this study, we examined whether levetiracetam has local peripheral antihyperalgesic/anti-edematous effects in the same model of localized inflammation and whether opioidergic, adrenergic, purinergic, 5-HTergic, and GABAergic receptors are involved in its antihyperalgesic action.
  
  
  METHODS
  Rats were intraplantarly (IPL) injected with carrageenan. A paw pressure test was used to determine the effect/s of (a) levetiracetam when applied IPL, on carrageenan-induced hyperalgesia, and (b) naloxone (a nonselective opioid receptor antagonist), CTAP (a selective μ-opioid receptor antagonist); yohimbine (a selective α(2)-adrenoceptor antagonist), BRL 44408 (a selective α(2A)-adrenoceptor antagonist), MK-912 (a selective α(2C)-adrenoceptor antagonist); caffeine (a nonselective adenosine receptor antagonist), DPCPX (a selective adenosine A(1) receptor antagonist); methysergide (a nonselective 5-HT receptor antagonist), GR 127935 (a selective 5-HT(1B/1D) receptor antagonist); and bicuculline (a selective GABA(A) receptor antagonist), all applied IPL, on the levetiracetam-induced antihyperalgesia. Moreover, levetiracetam's influence on paw inflammatory edema was measured by plethysmometry.
  
  
  RESULTS
  Levetiracetam (200-1000 nmol/paw) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia and edema induced by carrageenan. Naloxone (75-300 nmol/paw), CTAP (1-5 nmol/paw); yohimbine (130-520 nmol/paw), BRL 44408 (50-200 nmol/paw), MK-912 (5-20 nmol/paw); caffeine (500-1500 nmol/paw), DPCPX (3-30 nmol/paw); methysergide (10-100 nmol/paw) and GR 127935 (50-200 nmol/paw); but not bicuculline (400 nmol/paw), significantly depressed the antihyperalgesic effects of levetiracetam (1000 nmol/paw). The effects of levetiracetam and antagonists were attributed to local peripheral effects because they were not observed after administration into the contralateral hind-paw.
  
  
  CONCLUSIONS
  Our results show that levetiracetam produces local peripheral antihyperalgesic and anti-edematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral μ-opioid, α2A,C-adrenergic, A1 adenosine, and 5-HT1B/1D receptors, but not by GABAA receptors. These findings could contribute toward a better understanding of the analgesic effects of levetiracetam, and improved treatments of inflammatory pain with a lower incidence of systemic side effects and drug interactions of levetiracetam.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, P.O. Box 146, 11221, Belgrade, Serbia. racabbr@eunet.rs
authors.forename: Radica M
authors.initials: RM
authors.lastname: Stepanović-Petrović
authors.forename: Ana M
authors.initials: AM
authors.lastname: Micov
authors.forename: Maja A
authors.initials: MA
authors.lastname: Tomić
authors.forename: Nenad D
authors.initials: ND
authors.lastname: Ugrešić
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002351:Carrageenan; D004347:Drug Interactions; D004487:Edema / Q000188:drug therapy; D005528:Foot / Q000473:pathology; D018756:GABA Antagonists / Q000494:pharmacology; D006614:Hindlimb / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D000077287:Levetiracetam; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D010525:Peripheral Nerves / Q000187:drug effects*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010991:Plethysmography; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000779:Anesthetics, Local; D018756:GABA Antagonists; D011957:Receptors, Opioid; D012702:Serotonin Antagonists; D000077287:Levetiracetam; D002351:Carrageenan; D010889:Piracetam