The effects of the selective and non-peptide CXCR2 receptor antagonist SB225002 on acute and long-lasting models of nociception in mice.
This study evaluated the antinociceptive effects of the selective and non-peptide CXCR2 antagonist SB225002 in mouse models of pain. As assessed in different tests of spontaneous nociception, intraperitoneal (i.p.) administration of SB225002 caused consistent and dose-related reduction of acetic acid-induced abdominal constrictions, whereas it did not significantly affect the nociception evoked by formalin, capsaicin, glutamate or phorbol ester acetate (PMA). Systemic treatment with SB225002 strikingly reduced the spontaneous nociception induced by 8-bromo-cAMP (8-Br-cAMP), or mechanical hypernociception induced by prostaglandin E(2) (PGE(2)), epinephrine, or the keratinocyte-derived chemokine (KC). In the carrageenan model, SB225002 markedly reduced mechanical hypernociception when administered by i.p., intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes, or even when co-administered with carrageenan into the mouse paw, indicating peripheral and central sites of action for SB225002. In addition, i.p. treatment with SB225002 significantly attenuated the increase in MPO activity or the elevation of IL-1beta, TNFalpha or KC levels following carrageenan injection. In the persistent models of pain evoked by complete Freund's adjuvant (CFA) or by the partial ligation of the sciatic nerve (PLSN), the repeated administration of SB225002 displayed prominent and long-lasting antinociceptive effects. Notably, SB225002 did not evoke unspecific central effects, as evaluated in the open-field and rota-rod tests, or even in the latency responses for thermal stimuli. Our data confirm the previous notion on the critical role exerted by chemokines in pain, indicating that selective CXCR2 antagonists, such as SB225002, might well represent interesting and innovative alternatives for the management of both acute and chronic pain.
Manjavachi
Marianne N
MN
Departament of Pharmacology, Campus Universitário, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Quintão
Nara L M
NL
Campos
Maria Martha
MM
Deschamps
Isa K
IK
Yunes
Rosendo A
RA
Nunes
Ricardo J
RJ
Leal
Paulo C
PC
Calixto
João B
JB
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D019342:Acetic Acid; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002351:Carrageenan; D018925:Chemokines / Q000378:metabolism; D005557:Formaldehyde; D005620:Freund's Adjuvant; D007202:Indicators and Reagents; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010812:Physical Stimulation; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D007202:Indicators and Reagents; D053583:Interleukin-1beta; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; C112019:SB 225002; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002351:Carrageenan; D005620:Freund's Adjuvant; D009195:Peroxidase; D019342:Acetic Acid