Fructose-1,6-bisphosphate reduces inflammatory pain-like behaviour in mice: role of adenosine acting on A1 receptors.
OBJECTIVE
D-Fructose-1,6-bisphosphate (FBP) is an intermediate in the glycolytic pathway, exerting pharmacological actions on inflammation by inhibiting cytokine production or interfering with adenosine production. Here, the possible antinociceptive effect of FBP and its mechanism of action in the carrageenin paw inflammation model in mice were addressed, focusing on the two mechanisms described above.


METHODS
Mechanical hyperalgesia (decrease in the nociceptive threshold) was evaluated by the electronic pressure-metre test; cytokine levels were measured by elisa and adenosine was determined by high performance liquid chromatography.


RESULTS
Pretreatment of mice with FBP reduced hyperalgesia induced by intraplantar injection of carrageenin (up to 54%), tumour necrosis factor alpha (40%), interleukin-1 beta (46%), CXCL1 (33%), prostaglandin E(2) (41%) or dopamine (55%). However, FBP treatment did not alter carrageenin-induced cytokine (tumour necrosis factor alpha and interleukin-1 beta) or chemokine (CXCL1) production. On the other hand, the antinociceptive effect of FBP was prevented by systemic and intraplantar treatment with an adenosine A(1) receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine), suggesting that the FBP effect is mediated by peripheral adenosine acting on A(1) receptors. Giving FBP to mice increased adenosine levels in plasma, and adenosine treatment of paw inflammation presented a similar antinociceptive mechanism to that of FBP.


CONCLUSIONS
In addition to anti-inflammatory action, FBP also presents an antinociceptive effect upon inflammatory hyperalgesia. Its mechanism of action seems dependent on adenosine production but not on modulation of hyperalgesic cytokine/chemokine production. In turn, adenosine acts peripherally on its A(1) receptor inhibiting hyperalgesia. FBP may have possible therapeutic applications in reducing inflammatory pain.
Valério
D A
DA
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Ferreira
F I
FI
Cunha
T M
TM
Alves-Filho
J C
JC
Lima
F O
FO
De Oliveira
J R
JR
Ferreira
S H
SH
Cunha
F Q
FQ
Queiroz
R H
RH
Verri
W A
WA
D000241:Adenosine / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005635:Fructosediphosphates / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D010147:Pain Measurement; D043682:Receptor, Adenosine A1 / Q000378:metabolism
D000700:Analgesics; D005635:Fructosediphosphates; D043682:Receptor, Adenosine A1; D000241:Adenosine; C029063:fructose-1,6-diphosphate