No abstract

Through activation of the A1 adenosine receptors (A1Rs) at both the central and peripheral level, adenosine produces antinociception in a wide range of tests. However, the mechanisms involved in the peripheral effect are still not fully understood. Therefore, the mechanisms by which peripheral activation of A1Rs reduces inflammatory hypernociception (a decrease in the nociceptive threshold) were addressed in the present study. Immunofluorescence of rat dorsal root ganglion revealed significant expression of A1Rs in primary sensory neurons associated with nociceptive pathways. Functionally, peripheral activation of A1Rs reduced inflammatory hypernociception because intraplantar (i.pl.) administration of an A1R antagonist (DPCPX) enhanced carrageenan-induced hypernociception. On the other hand, local (paw) administration of CPA (a selective A1R agonist) reversed mechanical hypernociception induced by carrageenan or by the directly acting hypernociceptive mediator prostaglandin E(2) (PGE(2)). Down-regulation of A1Rs expression in primary nociceptive neurons by intrathecal treatment with antisense oligodeoxinucleotides significantly reduced peripheral antinociceptive action of CPA. Direct blockade of PGE(2) inflammatory hypernociception by the activation of A1Rs depends on the nitric oxide/cGMP/Protein Kinase G/KATP signaling pathway because the peripheral antinociceptive effect of CPA was prevented by pretreatment with inhibitors of neuronal nitric oxide synthase (N-propyl-l-arginine), guanylyl cyclase (ODQ), and Protein Kinase G (KT5823) as well as with a KATP blocker (glibenclamide). However, this effect of CPA was not reduced by naloxone, excluding the participation of endogenous opioids. These results suggest that the peripheral activation of A1R plays a role in the regulation of inflammatory hypernociception by a mechanism that involves the NO/cGMP/PKG/KATP intracellular signaling pathway.

Bergenin (1) is a C-glucoside of 4-O-methylgallic acid with known antiarthritic activity attributed to modulation of cytokine production. The present study was undertaken to evaluate whether 1 has antinociceptive properties in models of inflammatory pain and to investigate its possible mechanisms of action. Pretreatment with 1 (12.5-100 mg/kg, ip) produced a dose-related inhibition of acetic acid-induced writhing in mice. Furthermore, treatment with 1 (50 and 100 mg/kg) inhibited both the early and late phases in a formalin test. In addition, 1 (50 and 100 mg/kg, ip) inhibited mechanical hyperalgesia, edema, and paw production of hyperalgesic cytokines (TNF-α and IL-1β) induced by complete Freund's adjuvant. However, the local production of IL-10, an anti-inflammatory cytokine, was not altered by 1 (100 mg/kg, ip). Treatment with 1 produced a similar profile of antinociception in wild-type and IL-10-deficient mice. Mice treated with 1 did not show any motor performance alterations or apparent systemic toxicity. The results presented herein demonstrate that bergenin has consistent antinociceptive and anti-inflammatory properties, acting by the inhibition of IL-1β and TNF-α production, and suggest its potential for the control of inflammatory pain.

It was concluded that the LPT presented positive effects on inflammatory infiltration reduction and accelerated the inflammation process, mainly with IR laser irradiation. The number of synovial cell layers was reduced on irradiated group.