Evidence for the involvement of glutamatergic and GABAergic systems and protein kinase A pathway in the antinociceptive effect caused by p-methoxy-diphenyl diselenide in mice.
The present study investigated the antinociceptive effect of p-methoxy-diphenyl diselenide (MeOPhSe)(2), a simple organochalcogenide, in chemical and thermal behavioural models of nociception in mice, without accompanying changes in ambulation when assessed in an open field. This compound given by oral route (p.o.) produced antinociception when assessed on acetic acid-induced visceral nociception, with mean ID(50) value of 9.64 (3.28-28.35) mg/kg. In addition, the per oral administration of (MeOPhSe)(2) exhibited significant inhibition of the neurogenic nociception induced by intraplantar (i.pl.) injection of capsaicin, with mean ID(50) value of 16.29 (11.43-23.22) mg/kg. (MeOPhSe)(2) showed an antinociceptive effect when measured by the tail-immersion and hot-plate tests. Likewise, compound inhibited both neurogenic and inflammatory phases of the overt nociception caused by i.pl injection of formalin, with mean ID(50) values of 22.32 (17.84-27.92) and 19.65 (13.67-28.24) mg/kg, respectively. (MeOPhSe)(2) reduced the nociception produced by i.pl. injection of glutamate and 8-bromo-cAMP (8-Br-cAMP, a protein kinase A [PKA] activator), with mean ID(50) values of 11.05 (7.12-17.15) and 8.72 (5.42-14.02) mg/kg, respectively. (MeOPhSe)(2) also reduced formalin-, glutamate-, induced paw oedema formation. A marked inhibition of the biting behaviour induced by intrathecal (i.t.) injection of glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and (+/-)-1 aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) was caused by (MeOPhSe)(2). However, (MeOPhSe)(2) completely failed to affect the nociception induced by i.t. injection of N-methyl-D-aspartate (NMDA; 450 pmol/site) and kainate (110 pmol /site). The antinociceptive effect caused by (MeOPhSe)(2) was blocked by picrotoxin (a chloride ion channel blocker) and bicucculine (a specific GABA(A) receptor antagonist) but not by phaclofen (a specific GABA(B) receptor antagonist) in the hot-plate test. Together, these results indicate that (MeOPhSe)(2) produces antinociception in several models of nociception through mechanisms that involve an interaction with glutamatergic and GABAergic systems, as well as the inhibition of protein kinase A pathway.
Pinto
Larissa Garcia
LG
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil.
Jesse
Cristiano Ricardo
CR
Nogueira
Cristina Wayne
CW
Savegnago
Lucielli
L
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D019342:Acetic Acid; D000700:Analgesics; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D002211:Capsaicin; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D020536:Enzyme Activators / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000502:physiology; D005260:Female; D005557:Formaldehyde; D018698:Glutamic Acid / Q000502:physiology*; D006358:Hot Temperature; D007101:Immersion / Q000503:physiopathology; D007278:Injections, Spinal; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000523:psychology; D011930:Reaction Time; D015398:Signal Transduction / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000700:Analgesics; D001555:Benzene Derivatives; D020536:Enzyme Activators; D018846:Excitatory Amino Acids; D016566:Organoselenium Compounds; C528548:p-methoxy-diphenyl diselenide; D005557:Formaldehyde; D015124:8-Bromo Cyclic Adenosine Monophosphate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D019342:Acetic Acid; D002211:Capsaicin