title: CB1 and CB2 cannabinoid receptor agonists induce peripheral antinociception by activation of the endogenous noradrenergic system.
abstract: BACKGROUND
  Cannabinoid agonists induce norepinephrine release in central, spinal, and peripheral sites. Previous studies suggest an interaction between the cannabinoid and adrenergic systems on antinociception. In this study, we sought to verify whether the CB1 and CB2 cannabinoid receptor agonists anandamide and N-palmitoyl-ethanolamine (PEA), respectively, are able to induce peripheral antinociception via an adrenergic mechanism.
  
  
  METHODS
  All drugs were administered locally into the right hindpaw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2 (2 μg).
  
  
  RESULTS
  Anandamide, 12.5 ng/paw, 25 ng/paw, and 50 ng/paw elicited a local peripheral antinociceptive effect that was antagonized by CB1 cannabinoid receptor antagonist AM251, 20 µg/paw, 40 µg/paw, and 80 µg/paw, but not by CB2 cannabinoid receptor antagonist AM630, 100 µg/paw. PEA, 5 µg/paw, 10 µg/paw, and 20 µg/paw, elicited a local peripheral antinociceptive effect that was antagonized by AM630, 25 µg/paw, 50 µg/paw, and 100 µg/paw, but not by AM251, 80 µg/paw. Antinociception induced by anandamide or PEA was antagonized by the nonselective α2 adrenoceptor antagonist yohimbine, 05 µg/paw, 10 µg/paw, and 20 µg/paw, and by the selective α2C adrenoceptor antagonist rauwolscine, 10 µg/paw, 15 µg/paw, and 20 µg/paw, but not by the selective antagonists for α2A, α2B, and α2D adrenoceptor subtypes, 20 μg/paw. The antinociceptive effect of the cannabinoids was also antagonized by the nonselective α1 adrenoceptor antagonist prazosin, 0.5 µg/paw, 1 µg/paw, and 2 µg/paw, and by the nonselective β adrenoceptor antagonist propranolol, 150 ng/paw, 300 ng/paw, and 600 ng/paw. Guanethidine, which depletes peripheral sympathomimetic amines (30 mg/kg/animal, once a day for 3 days), restored approximately 70% the anandamide-induced and PEA-induced peripheral antinociception. Furthermore, acute injection of the norepinephrine reuptake inhibitor reboxetine, 30 µg/paw, intensified the antinociceptive effects of low-dose anandamide, 12.5 ng/paw, and PEA, 5 µg/paw.
  
  
  CONCLUSIONS
  This study provides evidence that anandamide and PEA induce peripheral antinociception activating CB1 and CB2 cannabinoid receptors, respectively, stimulating an endogenous norepinephrine release that activates peripheral adrenoceptors inducing antinociception.
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, ICB-UFMG, Av. Antonio Carlos, 6627, Pampulha, CEP 31.270-100, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Thiago R L
authors.initials: TR
authors.lastname: Romero
authors.forename: Livia C
authors.initials: LC
authors.lastname: Resende
authors.forename: Luciana S
authors.initials: LS
authors.lastname: Guzzo
authors.forename: Igor D G
authors.initials: ID
authors.lastname: Duarte
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000577:Amides; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D015232:Dinoprostone; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D010169:Palmitic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000577:Amides; D000700:Analgesics; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D004983:Ethanolamines; D009025:Morpholines; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D015016:Yohimbine; C005958:palmidrol; D000077593:Reboxetine; D011433:Propranolol; D015232:Dinoprostone; C078814:anandamide; D009638:Norepinephrine; D011224:Prazosin