AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors

G. La Rana, R. Russo, G. D'Agostino, O. Sasso, G. Mattace Raso, A. Iacono, R. Meli, D. Piomelli, A. Calignano

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Abstract

Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.
Original languageEnglish
Pages (from-to)521-529
Number of pages9
JournalNeuropharmacology
Volume54
Issue number3
Early online date7 Nov 2007
DOIs
Publication statusPublished - Mar 2008

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Cannabinoid Receptors
Calcitonin Gene-Related Peptide
Neuralgia
Substance P
Evans Blue
Cannabinoids
Prostaglandins
Blood Vessels
Nitric Oxide
Cannabinoid Receptor Agonists
Pain
Peripheral Nerve Injuries
Unmyelinated Nerve Fibers
Capsaicin
Capillary Permeability
Enzyme Inhibitors
Sciatic Nerve
Constriction
Ligation
Edema

Keywords

  • analgesics
  • analysis of variance
  • animals
  • arachidonic acids
  • benzoxazines
  • capillary permeability
  • disease models, animal
  • dose-response relationship, drug
  • enzyme inhibitors
  • Evans blue
  • hyperalgesia
  • male
  • morpholines
  • motor activity
  • naphthalenes
  • pain measurement
  • pain threshold
  • plasma
  • rats
  • rats, wistar
  • reaction time
  • receptors, cannabinoid
  • sciatica

Cite this

AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat : role for cannabinoid receptors. / La Rana, G.; Russo, R.; D'Agostino, G.; Sasso, O.; Raso, G. Mattace; Iacono, A.; Meli, R.; Piomelli, D.; Calignano, A.

In: Neuropharmacology, Vol. 54, No. 3, 03.2008, p. 521-529.

Research output: Contribution to journalArticle

La Rana, G, Russo, R, D'Agostino, G, Sasso, O, Raso, GM, Iacono, A, Meli, R, Piomelli, D & Calignano, A 2008, 'AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors' Neuropharmacology, vol. 54, no. 3, pp. 521-529. https://doi.org/10.1016/j.neuropharm.2007.10.021
La Rana, G. ; Russo, R. ; D'Agostino, G. ; Sasso, O. ; Raso, G. Mattace ; Iacono, A. ; Meli, R. ; Piomelli, D. ; Calignano, A. / AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat : role for cannabinoid receptors. In: Neuropharmacology. 2008 ; Vol. 54, No. 3. pp. 521-529.
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abstract = "Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.",
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AU - Russo, R.

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AU - Sasso, O.

AU - Raso, G. Mattace

AU - Iacono, A.

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N2 - Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.

AB - Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.

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KW - benzoxazines

KW - capillary permeability

KW - disease models, animal

KW - dose-response relationship, drug

KW - enzyme inhibitors

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KW - hyperalgesia

KW - male

KW - morpholines

KW - motor activity

KW - naphthalenes

KW - pain measurement

KW - pain threshold

KW - plasma

KW - rats

KW - rats, wistar

KW - reaction time

KW - receptors, cannabinoid

KW - sciatica

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DO - 10.1016/j.neuropharm.2007.10.021

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JO - Neuropharmacology

JF - Neuropharmacology

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