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.
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.
Martucci
Cataldo
C
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.
Trovato
Anna Elisa
AE
Costa
Barbara
B
Borsani
Elisa
E
Franchi
Silvia
S
Magnaghi
Valerio
V
Panerai
Alberto E
AE
Rodella
Luigi F
LF
Valsecchi
Anna Elisa
AE
Sacerdote
Paola
P
Colleoni
Mariapia
M
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
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