Inosine reduces pain-related behavior in mice: involvement of adenosine A1 and A2A receptor subtypes and protein kinase C pathways.

Inosine, an endogenous purine, is the first metabolite of adenosine in a reaction catalyzed by adenosine deaminase. This study aimed to investigate the antinociceptive effects of inosine against several models of pain in mice and rats. In mice, inosine given by systemic or central routes inhibited acetic acid-induced nociception. Furthermore, inosine also decreased the late phase of formalin-induced licking and the nociception induced by glutamate. Inosine produced inhibition (for up to 4 h) of mechanical allodynia induced by complete Freund's adjuvant (CFA) injected into the mouse's paw. Given chronically for 21 days, inosine reversed the mechanical allodynia caused by CFA. Moreover, inosine also reduced the thermal (cold stimuli) and mechanical allodynia caused by partial sciatic nerve ligation (PSNL) for 4 h; when inosine was chronically administered, it decreased the mechanical allodynia induced by PSNL for 22 days. Antinociception caused by inosine in the acetic acid test was attenuated by treatment of mice with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A(1) receptor antagonist), 8-phenyltheophylline (8-PT; a nonselective adenosine A(1) receptor antagonist), and 4-{2- [7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl- amino]ethyl}phenol (ZM241385; a selective adenosine A(2A) receptor antagonist). In rats, inosine inhibited the mechanical and heat hyperalgesia induced by bradykinin and phorbol 12-myristate 13-acetate, without affecting similar responses caused by prostaglandin E(2) or forskolin. These results indicate that inosine induces antinociceptive, antiallodynic, and antihyperalgesic effects in rodents. The precise mechanisms through which inosine produces antinociception are currently under investigation, but involvement of adenosine A(1) and A(2A) receptors and blockade of the protein kinase C pathway seem to largely account for inosine's antinociceptive effect.

Evidence for the involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of memantine in mice.

This study investigated the involvement of the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect of an acute administration of memantine in the forced swimming test (FST) in mice, since this signaling pathway is supposed to play a significant role in depression. The antidepressant-like effect of memantine (3 mg/kg, i.p.) was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) or S-nitroso-N-acetyl-penicillamine (SNAP, 25 microg/site, i.c.v.), but not with d-arginine (750 mg/kg, i.p.).The treatment of mice with NG-nitro-L-arginine (L-NNA, 0.03 and 0.3 mg/kg, i.p.) potentiated the effect of a subeffective dose of memantine (0.3 mg/kg, i.p.) in the FST. Moreover, the pretreatment of mice with (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one) (ODQ, 30 pmol/site, i.c.v.) produced a synergistic antidepressant-like effect with subeffective doses of memantine (0.3 and 1 mg/kg, i.p.) in the FST. Furthermore, the reduction in the immobility time elicited by memantine (3 mg/kg, i.p.) in the FST was prevented by pretreatment with sildenafil (5 mg/kg, i.p.). Taken together, the results demonstrate that memantine produced an antidepressant-like effect in the FST that seems to be mediated through an interaction with the L-arginine-NO-cGMP pathway.

Involvement of PKA, MAPK/ERK and CaMKII, but not PKC in the acute antidepressant-like effect of memantine in mice.

This study investigated the cellular signaling pathways involved in the acute antidepressant-like action of memantine in the forced swimming test (FST) in mice. The immobility time in the FST was reduced by memantine (3-10 mg/kg, i.p.). The anti-immobility effect of memantine (3 mg/kg, i.p.) was prevented by pretreatment with H-89 (1 microg/site, i.c.v., an inhibitor of PKA), PD098059 (5 microg/site, i.c.v., an inhibitor of MAPK/ERK), KN-62 (1 microg/site, i.c.v., an inhibitor of CaMKII), but not with chelerythrine (1 microg/site, i.c.v., an inhibitor of PKC). Taken together, these results firstly demonstrate that the acute antidepressant-like effect of memantine seems to be dependent on the cellular signaling modulated by PKA, CaMKII and MAPK/ERK, but not by PKC.