title: The purinergic antagonist PPADS reduces pain related behaviours and interleukin-1 beta, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice.
abstract: Neuropathic pain consequent to peripheral injury is associated with local inflammation and overexpression of nitric oxide synthases (NOS) and inflammatory cytokines in locally recruited macrophages, Schwann and glial cells. We investigated the time course and localization of nitric oxide synthases (NOS) and cytokines in the central (spinal cord and thalamus) and peripheral nervous system (nerve and dorsal root ganglia), in a mouse model of mononeuropathy induced by sciatic nerve chronic constriction injury. ATP is recognized as an endogenous pain mediator. Therefore we also evaluated the role of purinergic signalling in pain hypersensitivity employing the P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), on pain behaviour, NOS and cytokines. The PPADS daily administration starting on day 3 after injury dose- and time-dependently decreased both tactile allodynia and thermal hyperalgesia. PPADS (25mg/kg) completely reversed nociceptive hypersensitivity and simultaneously reduced the increased NO/NOS system and IL-1beta in both peripheral (injured sciatic nerve and L4-L6 ipsilateral dorsal root ganglia) and central steps of nervous system (L4-L6 spinal cord and thalamus) involved in pain signalling. IL-6 was overexpressed only in the peripheral nervous system and PPADS prolonged administration reduced it in sciatic nerve. In conclusion, we hypothesize that NO/NOS and IL-1beta have a pronociceptive role in this neuropathy model, and that purinergic antagonism reduces pain hypersensitivity by inhibiting their overactivity.
authors: Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, via Vanvitelli 32, 20129 Milano, Italy Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milano, Italy Department of Endocrinology and Center of Excellence of Neurodegenerative Diseases, University of Milano, 20133 Milano, Italy Division of Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
authors: Cataldo
authors: C
authors: Martucci
authors: Anna Elisa
authors: AE
authors: Trovato
authors: Barbara
authors: B
authors: Costa
authors: Elisa
authors: E
authors: Borsani
authors: Silvia
authors: S
authors: Franchi
authors: Valerio
authors: V
authors: Magnaghi
authors: Alberto E
authors: AE
authors: Panerai
authors: Luigi F
authors: LF
authors: Rodella
authors: Anna Elisa
authors: AE
authors: Valsecchi
authors: Paola
authors: P
authors: Sacerdote
authors: Mariapia
authors: M
authors: Colleoni
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016503:Drug Delivery Systems; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010146:Pain / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018048:Receptors, Purinergic P2 / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate; D018048:Receptors, Purinergic P2; D000093242:Interleukin-6 Inhibitors; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse