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: Radica M Stepanović-Petrović, Ana M Micov, Maja A Tomić, Nenad D Ugrešić
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 115 Issue 6 Pg. 1457-66 (Dec 2012) ISSN: 1526-7598 [Electronic] United States
• PMID: 23144430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine A1 Receptor Antagonists
• Adrenergic alpha-Antagonists
• Anesthetics, Local
• GABA Antagonists
• Receptors, Opioid
• Serotonin Antagonists
• Levetiracetam
• Carrageenan
• Piracetam

Topics

• Adenosine A1 Receptor Antagonists (pharmacology)
• Adrenergic alpha-Antagonists (pharmacology)
• Anesthetics, Local (pharmacology, therapeutic use)
• Animals
• Carrageenan
• Drug Interactions
• Edema (drug therapy)
• Foot (pathology)
• GABA Antagonists (pharmacology)
• Hindlimb (pathology)
• Hyperalgesia (chemically induced, complications, drug therapy)
• Inflammation (chemically induced, complications, drug therapy)
• Levetiracetam
• Male
• Pain (chemically induced, drug therapy, etiology)
• Peripheral Nerves (drug effects)
• Piracetam (analogs & derivatives, pharmacology, therapeutic use)
• Plethysmography
• Rats
• Rats, Wistar
• Receptors, Opioid (drug effects)
• Serotonin Antagonists (pharmacology)