Category Archives: Pain Management

CO 047: ANTINOCICEPTIVE ACTIVITY OF MANGIFERIN IN FORMALIN PAIN

J Pharm Pharmacogn Res 2(Suppl. 1): S26, 2014

Special supplement with the abstract book of LATINFARMA 2013

Oral Communication

CO 047: ANTINOCICEPTIVE ACTIVITY OF MANGIFERIN IN FORMALIN PAIN

Espinoza de los Monteros-Zuñiga Aa, Cervantes-Durán Cb, Lozada-García MCa, Izquierdo-Sánchez Ta, Godínez-Chaparro Ba,c.

aDepto. Sistemas Biológicos, División de Ciencias Biológicas y de la Salud. Universidad Autónoma Metropolitana-Xochimilco (UAM-X).
bDepto. Farmacobiología, Centro de Investigación y de Estudios Avanzados, Sede Sur. (CINVESTAV-Sur), México.
cInstituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro, 76230, México. E-mail: tizquier@correo.xoc.uam.mx
Abstract

Introduction: Mangiferin is a glucoxylxanthone present in the aqueous extract of Mangifera indica L., the extract has shown multiple pharmacological effects as antioxidant, anti-inflammatory and antinociceptive effects. The present study was undertaken to determine the possible antinociceptive activity of mangiferin in rats, as well as its possible mechanisms of action.

Material and methods: Nociceptive behavior was quantified as the numbers of flinches of the injected paw during 1-min per 5 min, up to 60 min after 1% formalin injection. Magniferin was given orally (1-30 mg/kg), locally (1-30 µg/paw in 50 µL) or intrathecally (1-30 µg/rat in 10 µL) 30 min and 10 min before, respectively, 1% formalin injection in the dorsum paw. Diclofenac was used as a positive control. Animals were administered with vehicle or methiothepin (30 µg/paw), naloxone (5-50 µg/paw), naltrindole (0.1-1 µg/paw), 5-GNTI (0.1-1 µg/paw), L-NAME (10-100 µg/paw), ODQ (5-50 µg/paw) or glibenclamide (10-100 µg/paw) were administrated 20 min before mangiferin (30 µg/paw) which was given 10 min before of 1% formalin injection.

Results: The ipsilateral local peripheral (1-30 µg/paw), intrathecal (130 µg/rat) and oral (1-30 mg/kg) administration of mangiferin produced a dose-dependent reduction in formalin-induced nociception. The antinociceptive effect of this drug was similar to induced by diclofenac after oral and local peripheral administration. The local peripheral antinociceptive effect in the formalin test was blocked by naloxone (50 μg/paw), naltrindole (1 μg/paw), 5-GNTI (1 µg/paw), L-NAME (100 μg/paw), (50 μg/paw) and glibenclamide (50 μg/paw), but not by methiothepin (30 μg/paw).

Conclusions: These data suggest, that the antinociceptive effect induced by mangiferin are mediated by the modulation of peripheral opioidergic system involving the activation of δ, κ, and probably μ, receptors, but not serotonergic receptors. Also suggests that mangiferin activates the NO-cyclic GMP-ATP-sensitive K+ channels pathway related to modulate local peripheral nociceptive effect in rats.

CO 046: MANGIFERIN FOR THE MANAGEMENT OF PAIN: ADVANTAGES OF ITS TRANSCIENT AND LONG TERM NEUROMODULATORY EFFECTS

J Pharm Pharmacogn Res 2(Suppl. 1): S25, 2014

Special supplement with the abstract book of LATINFARMA 2013

Oral Communication

CO 046: MANGIFERIN FOR THE MANAGEMENT OF PAIN: ADVANTAGES OF ITS TRANSCIENT AND LONG TERM NEUROMODULATORY EFFECTS

Garrido BB1, Castro M1, Rodeiro I2, Hernández I2, Pardo Z1, Menédez R1, Delgado R1.

1Drug Research and Development Center, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, Plaza de la Revolución, La Habana, Cuba.
2Center of Marine Bioproducts, Loma y 37, CP 10300, Nuevo Vedado, La Habana, Cuba.
Abstract

Introduction: Neuroimmune activation and nitroxidative stress are implicated in glutamatergic system dysfunction, which induces excytotoxic neural damage, desinhibition and central hyperexcitability subjacent in chronic pain. Mangiferin (MG), a naturally occurring glucoxylxanthone isolated from the standard aqueous bark extract of Mangifera indica L. shows inhibition of NF-κB signaling pathway, neuroprotective effects, antioxidant activity and it is able to limit microglial activation. Besides, reversible mono-amine oxidase (MAO) inhibitory activity is reported by xanthones, an effect that may modulate catecholamine concentration in the synaptic cleft modulating spinal nociceptive processing through the PAG/RVM/DLPT descending modulatory network. This conference focuses on unifying the cumulus of evidences around the MG effects on several animal models of pain, hypothesizing about their mechanism of actions according to a pharmacological approach.

Results: The acute administration of MG (10-100 mg/kg, i.p.) decreases licking/biting behaviors exclusivity in tonic phase of formalin 5% test. Pre-treatment with naloxone, a non selective opioid antagonist and yohimbine a selective α2 adrenergic antagonist partially reversed this effect. Intrathecal MG injection also reproduced the same behaviors. In addition, MG decreases visceral nociceptive behaviors in ovariectomized (OVX)-induced hyperalgesia in rats, which show monoamine levels decreased in brain. Preventive repeated systemic administration of MG before sciatic chronic constriction injury (CCI) in rats reduced mechanical hyperalgesia at 7 and 14 days and also decreased the signs of Wallerian degeneration of the sciatic nerve. As well as, MG improved the PC-12 cellular viability (70%) exposure to glutamate-mediated excytotoxic injury. Likewise, oral acute and chronic administration of MG in rats with chronic post-ischemia pain (CPIP), a complex regional pain syndrome type I model, decreased mechanical allodynia from 2h of MG administration and IL-1β concentration in spinal cord homogenates. A long term antihyperalgesic effects, even after discontinuation of the medication, were observed.

Conclusions: MG may modulate pathological and persistent painful status, and its anti-hyperalgesic effect could be mediated, at least in part, in the spinal cord by opioid and noradrenergic transient mechanisms. Long term effects mediated by transcriptional changes could be implicated in peripheral and central pain mechanisms, especially central sensitization.

C 008: THE RATIONALE OF ANALGESIS COMBINATIONS

J Pharm Pharmacogn Res 2(Suppl. 1): S27, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 008: THE RATIONALE OF ANALGESIS COMBINATIONS

Granizo E.

Universidad Central de Ecuador.
Abstract

No single analgesic agent is perfect and no single analgesic can treat all types of pain. Oral fixed drug combinations analgesics potentially have a number of advantages over monotherapy, but these benefits can only be attained through careful design that is not the case in some available preparations.

A combination is most effective when the individual agents act through different analgesic mechanisms and act synergistically. The fixed-dose combinations analgesics are of value only when they have bee developed according to rationale pharmacokinetic and pharmacodynamic criteria.

This overview highlights the therapeutic potential of combining analgesic medications with different mechanisms of action like a NSAIDs drugs or acetaminophen with an opioid or tramadol.

C 007: PHENOTYPIC MODIFICATIONS OF PRIMARY AFFERENT NEURONS INNERVATING OSTEOARTHRITIC JOINTS

J Pharm Pharmacogn Res 2(Suppl. 1): S27, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 007: PHENOTYPIC MODIFICATIONS OF PRIMARY AFFERENT NEURONS INNERVATING OSTEOARTHRITIC JOINTS

Castro-Lopes JM, Adães S, Ferreira-Gomes J.

Department of Experimental Biology, Faculty of Medicine of the University of Porto and IBMC, Portugal.
Abstract

Chronic pain associated with osteoarthritis (OA) is highly prevalent, but its mechanisms are not fully understood, and the pharmacological control of OA-associated pain is far from optimal. In an attempt to further clarify the neuronal mechanisms underlying nociception in OA, we have performed a series of studies on primary afferent neurons innervating OA joints, using the experimental model of intra-articular injection of mono-sodium iodoacetate (MIA) in the knee joint of adult rats, which causes a destruction of the articular cartilage.

By using the neuronal tracer Fluorogold (FG), we observed a decrease of 37% in the number of neurons innervating OA joints as compared to control animals, although there was no reduction in the total number of neurons in the dorsal root ganglia (DRGs). However, there was a decrease in the number of small neurons and a small increase of medium-large neurons in OA animals. Given that neurogenesis was not found in the DRGs of OA animals, those observations indicated a phenomenon of neuronal hypertrophy.

Regarding neurochemical markers for subpopulations of primary afferent neurons, there was an increase in the percentage of CGRP positive (peptidergic) neurons that innervate OA joints. Such increase occurred in small and large neurons. Since this peptide is usually not expressed in large neurons, our observation in OA animals points to a phenomenon of hypertrophy of medium-small neurons that normally express CGRP, or a phenotypic alteration of large neurons. No differences between OA and control animals were observed in what concerns labelling for IB4 or NF200 (labelling non-peptidergic or large non-nociceptive primary afferent neurons, respectively).

The changes described above could suggest the existence of damages in neurons that innervate OA joints. Therefore, we studied the expression of ATF-3 and NPY in the DRGs, since its expression has been associated with peripheral neuronal damage. Both markers were expressed in DRG neurons three days after injection of MIA, a very early stage in the development of experimental OA, decreased at day 14 of development of OA, and there was a second wave of expression later. We have also observed expression of GAP-43, a marker of neuronal regeneration, in ATF-3 positive cells.

Together, our results suggest that primary afferents that innervate MIA-induced OA joints are damaged, which may trigger the activation of neuronal regeneration mechanisms. Further studies are needed to clarify to which extent these phenomena contribute to pain associated with OA.

C 006: BETWEEN HYPERTENSION AND PAIN

J Pharm Pharmacogn Res 2(Suppl. 1): S25, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 006: BETWEEN HYPERTENSION AND PAIN

Henrique Ferreira S.

School of Medicine of Ribeirão Preto, Department of Pharmacology, Campus USP, Brazil.
Abstract

In the present communication Prof Sergio Henrique Ferreira describes his personal trajectory in the Department of Pharmacology from the Ribeirão Preto Medical School. The discovery of bradykinin, Prof Rocha e Silva just received a sample of that he had previously described when he incubated Jararaca Venom together with blood plasma. The synthetic bradykinin however was much weaker than the blood plasma product, thus suggesting the presence in the Jararaca venom of a potentiating factor, named by us BPF, i.e. bradykinin potentiating factor. Thus, plasma contained an enzyme that inactivates bradykinin and by coincidence it was the same enzyme that was responsible for the conversion of angiotensin I to angiotensin II. Angiotensin II is the biological factor responsible for hypertensive activity of this peptide. The smallest peptide of BPF, PCALys-Tryp-Ala –Pro, was used as basis for the industrial development of the potent anti-hypertensive drugs, angiotensin converting enzyme inhibitors.  During the years of 64-67 working in London in the department of Prof J.R. Vane, I participated in the discovery of the mechanism of action of aspirin-like-drugs. I proposed that its analgesic action was due to the prevention of the stimulation of primary sensory neurons by mediators, particularly by prostaglandins. Recently we found that opiates have a peripheral analgesic effect by means of the stimulation of the Arginine/NO/GMPc pathway. This mechanism may stimulate the development of new analgesics.

PHARMACOLOGICAL MANAGEMENT OF NEUROPATHIC PAIN

J Pharm Pharmacogn Res 2(Suppl. 1): S114, 2014

Special supplement with the abstract book of LATINFARMA 2013

Plenary Lecture

PL 010: PHARMACOLOGICAL MANAGEMENT OF NEUROPATHIC PAIN

Granizo E.

Universidad Central de Ecuador.
Abstract

Patients with neuropathic pain are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. In the last years the scientific information on pharmacological treatment of neuropathic pain has increase considerably. In the present review we take into account some groups of drugs classified by their site and mechanism of action: peripheral receptors; b) peripherals nerve fibers, c) spinal pain modulators, d central descendent modulators (re-up take amines inhibitors) and opioids, tramadol. We will review the recommended first line treatment include certain antidepressants, gabapentinoids, and topic lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first –line use in select clinical circumstances. We consider useful to give some concepts of the guidelines and recommendations from “Consenso Latinoamericano para el Manejo del Dolor Neuropático”

Anti-hyperalgesic effect of M. indica extract

J Pharm Pharmacogn Res 2(2): 36-44, 2014.

Original Article | Artículo Original

Anti-hyperalgesic effect of Mangifera indica L. extract on the sciatic chronic constriction injury model in rats

[Efecto anti-hiperalgésico del extracto de Mangifera indica L. en el modelo de daño por constricción crónica del nervio ciático en ratas]

Bárbara B. Garrido-Suárez, Marian Castro Labrada, Nelson Merino, Odalys Valdés, René Delgado-Hernández

Grupo de Dolor del Laboratorio de Neurofarmacología, Centro de Investigación y Desarrollo de Medicamentos. Ave. 26 No. 1605 e/ Boyeros y Puentes Grandes, Nuevo Vedado, Plaza. Apdo. Postal 10600. La Habana, Cuba. * E-mail: beatriz.garrido@infomed.sld.cu
Abstract

Context: The aqueous extract of Mangifera indica L. stem bark (MSBE) shows antioxidant, anti-inflammatory and analgesic properties.
Aims: To test the MSBE in chronic constriction injury (CCI) of the sciatic nerve in rats, a classical model of neuropathic pain.
Methods: Given the possibility that some clinical effect of MSBE can appear only after its chronic administration, we designed a long term medication protocol with 500 mg/kg, p.o. or distilled water daily during 8 days from 9 days post-CCI. Pregabalin (10 mg/kg, p.o.) was used as reference drug. Sham CCI animals received vehicle. Behavioral tests were carried out before CCI, at 9 and 16 days after injury. A section of sciatic nerve, 5 mm distal to the ligature site was dissected for histopathological studies. A single oral similar dose or vehicle was administered to mononeuropathic rats, 14 days after surgery. Mechano-hyperalgesia and thermal hyperalgesia of the ipsilateral paw were determined using a modification of pin prick method and the unilateral hot plate, respectively before CCI, 0, 30, 60, 120 and 180 min post-administration.
Results: Repeated oral MSBE doses reduced nociceptive score, increased paw withdrawal latency and attenuated CCI-induced Wallerian degeneration-related changes involved in the hyperalgesic state of CCI rats. Likewise, MSBE shows significant mechanical and thermal anti-hyperalgesic effect from 1h after its single administration.
Conclusions: The study of MSBE should be focused in neuropathic pain models since this natural product could have a clinical relevance in the treatment of neuropathic pain syndromes.

Keywords: Hyperalgesia; mangiferin; neuropathic pain.

jppres_pdf_freeResumen

Contexto: El extracto acuoso de la corteza del árbol del mango Mangifera indica L (ECAM) muestra propiedades antioxidantes, anti-inflamatorias y analgésicas.
Objetivos: Evaluar el ECAM en el modelo de daño por constricción crónica del nervio ciático (CCI) en ratas, un modelo clásico de dolor neuropático.
Métodos: Dada la posibilidad de que algunos efectos clínicos del ECAM puedan aparecer tras su administración crónica, se diseñó un protocolo de suministro a largo plazo con dosis orales de ECAM 500 mg/kg, p.o. o agua destilada durante 8 días desde el día 9 post-CCI. Se utilizó la pregabalina (10 mg/kg, p.o.) como fármaco de referencia. Los animales falsos operados recibieron vehículo. Las pruebas conductuales fueron conducidas antes del CCI, a los 9 y 16 días post-CCI. Una sección del nervio ciático 5 mm distal a la ligadura fue disecada para los estudios histopatológicos. Se estableció un protocolo de administración única a la misma dosis o vehículo 14 días tras la cirugía. Se evaluó la hiperalgesia mecánica y térmica de la pata ipsilateral utilizando una modificación del método de pin prick y el plato caliente unilateral, respectivamente antes del CCI, 0, 30, 60, 120 y 180 min post-administración.
Resultados: ECAM suministrado a dosis repetidas redujo las escalas nociceptivas, incrementó la latencia de retirada de la pata y atenuó la degeneración Walleriana implicada en la hiperalgesia de las ratas CCI. Igualmente mostró efecto anti-hiperalgésico desde la primera hora tras su administración.
Conclusiones: El estudio del ECAM debería ser enfocado hacia los modelos de dolor neuropático ya que el producto podría tener relevancia clínica en el tratamiento de estos síndromes.

Palabras Clave: Dolor neuropático; hiperalgesia; mangiferina.

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Citation Format: Bárbara B. Garrido-Suárez, Marian Castro Labrada, Nelson Merino, Odalys Valdés, René Delgado-Hernández (2014) Anti-hyperalgesic effect of Mangifera indica L. extract on the sciatic chronic constriction injury model in rats. J Pharm Pharmacogn Res 2(2): 36-44.
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