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/antiedematous 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 mu-opioid receptor antagonist); yohimbine (a selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a selective alpha(2A)-adrenoceptor antagonist), MK-912 (a selective alpha(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-HT1B/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 hindpaw. CONCLUSIONS: Our results show that levetiracetam produces local peripheral antihyperalgesic and antiedematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral mu-opioid, alpha(2A,C)-adrenergic, A(1) adenosine, and 5-HT1B/1D receptors, but not by GABA(A) 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. (Anesth Analg, 2012;115:1457-66)
Source:
Anesthesia and Analgesia, 2012, 115, 6, 1457-1466Publisher:
- Lippincott Williams & Wilkins, Philadelphia
Funding / projects:
DOI: 10.1213/ANE.0b013e31826c7fc2
ISSN: 0003-2999
PubMed: 23144430
WoS: 000311593800031
Scopus: 2-s2.0-84870243260
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PharmacyTY - JOUR AU - Stepanović-Petrović, Radica AU - Micov, Ana AU - Tomić, Maja AU - Ugrešić, Nenad PY - 2012 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1679 AB - 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/antiedematous 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 mu-opioid receptor antagonist); yohimbine (a selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a selective alpha(2A)-adrenoceptor antagonist), MK-912 (a selective alpha(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-HT1B/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 hindpaw. CONCLUSIONS: Our results show that levetiracetam produces local peripheral antihyperalgesic and antiedematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral mu-opioid, alpha(2A,C)-adrenergic, A(1) adenosine, and 5-HT1B/1D receptors, but not by GABA(A) 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. (Anesth Analg, 2012;115:1457-66) PB - Lippincott Williams & Wilkins, Philadelphia T2 - Anesthesia and Analgesia T1 - The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model VL - 115 IS - 6 SP - 1457 EP - 1466 DO - 10.1213/ANE.0b013e31826c7fc2 ER -
@article{ author = "Stepanović-Petrović, Radica and Micov, Ana and Tomić, Maja and Ugrešić, Nenad", year = "2012", 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/antiedematous 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 mu-opioid receptor antagonist); yohimbine (a selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a selective alpha(2A)-adrenoceptor antagonist), MK-912 (a selective alpha(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-HT1B/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 hindpaw. CONCLUSIONS: Our results show that levetiracetam produces local peripheral antihyperalgesic and antiedematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral mu-opioid, alpha(2A,C)-adrenergic, A(1) adenosine, and 5-HT1B/1D receptors, but not by GABA(A) 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. (Anesth Analg, 2012;115:1457-66)", publisher = "Lippincott Williams & Wilkins, Philadelphia", journal = "Anesthesia and Analgesia", title = "The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model", volume = "115", number = "6", pages = "1457-1466", doi = "10.1213/ANE.0b013e31826c7fc2" }
Stepanović-Petrović, R., Micov, A., Tomić, M.,& Ugrešić, N.. (2012). The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model. in Anesthesia and Analgesia Lippincott Williams & Wilkins, Philadelphia., 115(6), 1457-1466. https://doi.org/10.1213/ANE.0b013e31826c7fc2
Stepanović-Petrović R, Micov A, Tomić M, Ugrešić N. The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model. in Anesthesia and Analgesia. 2012;115(6):1457-1466. doi:10.1213/ANE.0b013e31826c7fc2 .
Stepanović-Petrović, Radica, Micov, Ana, Tomić, Maja, Ugrešić, Nenad, "The Local Peripheral Antihyperalgesic Effect of Levetiracetam and Its Mechanism of Action in an Inflammatory Pain Model" in Anesthesia and Analgesia, 115, no. 6 (2012):1457-1466, https://doi.org/10.1213/ANE.0b013e31826c7fc2 . .