Isobolographic analysis of the dual-site synergism in the antinociceptive response of tramadol in the formalin test in rats

Pozos‐Guillén, Amaury; Aguirre-Bañuelos, Patricia; Arellano-Guerrero, Abraham; Castañeda‐Hernández, Gilberto; Hoyo‐Vadillo, Carlos; Pèrez‐Urizar, José

doi:10.1016/j.lfs.2006.07.029

Cited by 18 publications

(22 citation statements)

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“…Recent preclinical studies have showed that spinal plus supraspinal administration of acetaminophen (24) and intraplantar and intraperitoneal administration of tramadol (25) produced antinociception greater than that expected by simply the sum of individual doses.…”

Section: Discussionmentioning

confidence: 99%

Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

Mendizábal

Vásquez-Bahena

Jiménez-Andrade

et al. 2012

AAPS J

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Abstract. The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2 Local in generating the pain response compared to COX-2 CNS . Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.

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Section: Discussionmentioning

confidence: 99%

Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

Mendizábal

Vásquez-Bahena

Jiménez-Andrade

et al. 2012

AAPS J

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“…8 Moreover, it has been demonstrated conclusively that tramadol inhibits the activity of NMDA receptors expressed in Xenopus oocytes in vitro. 8,19 Furthermore, peripheral tramadol administered intraplantarily in rats reduces formalin-induced nociception in rats, 20 which is partially mediated by glutamate release.…”

Section: Discussionmentioning

confidence: 99%

“…20 Other possible mechanisms of local anesthetic action distinct from sodium channel blockade are unlikely, since tramadol has no effects on inhibitory glycine or gammaaminobutyric acid (GABA) receptors at clinically relevant concentrations. 7 Primary activity through opioid action is unlikely, since direct application of peripheral intraplantar naloxone does not reverse tramadol's effect on reducing heat-induced nociception, 10 and naloxone does not reverse tramadol's ability to block the licking response to formalin in the paw.…”

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confidence: 99%

“…7 Primary activity through opioid action is unlikely, since direct application of peripheral intraplantar naloxone does not reverse tramadol's effect on reducing heat-induced nociception, 10 and naloxone does not reverse tramadol's ability to block the licking response to formalin in the paw. 20 Thus, it is likely that tramadol produces its analgesic effects in the tail-flick test by blockade of sodium channels.…”

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confidence: 99%

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Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice

Wang

Chung

Whitehead

et al. 2010

Can J Anesth/J Can Anesth

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Purpose The use of peripheral tramadol to block pain has been advocated. However, since its actions in the periphery have not been elucidated fully, we tested the hypothesis that peripheral tramadol blocks peripheral glutamate-induced nociceptive behaviour in mice. Methods First, we compared the duration of paw licking after intraplantar (ipl.) glutamate administration, with and without tramadol, using a randomized blinded controlled design. Next, we established the half maximal effective concentrations (EC 50s ) for local tramadol and reference compound lidocaine in the hot water tail-flick latency test and the glutamate-induced paw allodynia assay. Results Tramadol reduced glutamate-induced paw licking from 33 ± 12 sec to 4 ± 4 sec (mean ± SD; t test, P \ 0.05; n = 6 per group). The tramadol and lidocaine EC 50 nerve conduction blocks in the tail did not differ significantly (84 ± 24 mM vs 69 ± 5 mM, respectively).Although tramadol reduced glutamate-induced allodynia (EC 50 , 46 ± 13 mM), lidocaine was more potent (EC 50 , 13 ± 5 mM; Dixon's up-and-down method; P \ 0.05). Tramadol was 2.5 times as effective at blocking nerve conduction in the tail compared with allodynia in the paw. Conclusions Local tramadol administration blocked nociceptive behaviour in mice induced by peripheral glutamate. Compared with lidocaine, the relative potency of tramadol was lower for blocking glutamate-induced allodynia than for sensory nerve conduction blockade, suggesting the activation of a pronociceptive receptor system in the periphery. RésuméObjectif L'utilisation de tramadol pe´riphe´rique a e´teṕ ropose´e pour bloquer la douleur. Cependant, comme nous ne connaissons pas pleinement ses actions sur les nerfs pe´riphe´riques, nous avons e´mis l'hypothe`se que le tramadol pe´riphe´rique bloquait les comportements nociceptifs provoque´s par le glutamate pe´riphe´rique chez la souris. Méthode Nous avons d'abord compare´la dure´e du le´chage de la patte apre`s une administration intraplantaire (ipl.) de glutamate, avec ou sans tramadol, en utilisant une me´thode contrôle´e randomise´e en aveugle. Ensuite, nous avons de´termine´les concentrations efficaces moyennes (CE 50 ) pour le tramadol administre´localement et un compose´de lidocaı¨ne comme re´fe´rence a`l'aide du test de latence du retrait de la queue et du test d'allodynie de la patte provoque´e par le glutamate. Résultats Le tramadol a re´duit le le´chage de patte provoque´par le glutamate de 33 ± 12 sec a`4 ± 4 sec (moyenne ± ET; test t, P \ 0,05; n = 6 par groupe). Les CE 50 pour le bloc de conduction nerveuse re´alise´avec le

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“…In basic research, several local mechanisms for Tramadol have been reported, such as its weak peripheral agonism over MOR (2), activation of adrenergic receptors (9), lowering of the activation of vallinoid receptor 1 (TRPV-1) (10), blocking N-methyl-D-aspartate (NMDA) receptors (11), favoring the opening of nonspecific voltagedependent potassium channels (12), acting in the nitric oxide pathway (13) or by direct blocking of sodium channels (14). Experimentally, this drug have been successful in the control of peripheral pain in animal nociception models (15)(16)(17). In humans, it is also effective as an anesthetic adjuvant for brachial plexus block (18,19), for tendon repair surgery (20) or even compared with several local anesthetics when applied subcutaneously (21,22).…”

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Peripheral Tramadol in Dentistry: A New Use for an Old Drug

Chavarría

Pozos

2016

Odovtos - Int J Dent Sc

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Tramadol is a well known central acting analgesic drug, used in a wide variety of treatments within health sciences; including dentistry. Due to its lack of anti-inflammatory action and some adverse effects related mainly to opioid receptors agonism, it is not use as a routine alternative; keeping mainly for patients allergic to non-steroideal anti-inflammatory drugs or as an adjuvant to manage severe odontogenic pain. Since new available evidence supports the possible analgesic effect of this drug when is applied locally in different sites, recent reports have been done to explore the same effect in the orofacial region, especially to improve the local management of odontogenic pain. This new perspective article summarize some of the current efforts develop to explore the peripheral Tramadol in dentistry; "a new use for an old drug". KEYWORDSOld drugs; Peripheral tramadol; Local analgesics. RESUMENEl Tramadol es un fármaco de acción central bien conocido, usado en una gran variedad de tratamientos dentro de las ciencias de la salud; y la odontología no es la excepción. Debido a su falta de acción antiinflamatoria y a varios efectos adversos asociados principalmente al agonismo de receptores opioides, este no es usado como una alternativa de rutina; y se mantiene principalmente para pacientes alérgicos a antiinflamatorios no esteroideos o como coadyuvante en el manejo de dolor odontogénico severo. Sin embargo, ya que nueva evidencia disponible apoya su posible efecto analgésico al aplicarse localmente en diferentes sitios, investigaciones recientes se han realizado tratando de explorar el mismo efecto en la región orofacial, especialmente para mejorar el manejo local del dolor odontogénico. Este artículo de "nueva perspectiva" resume algunos de los esfuerzos recientes desarrollados para explorar el Tramadol periférico en odontología; un nuevo uso para un viejo medicamente.

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Isobolographic analysis of the dual-site synergism in the antinociceptive response of tramadol in the formalin test in rats

Cited by 18 publications

References 30 publications

Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice

Peripheral Tramadol in Dentistry: A New Use for an Old Drug

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