Physical exercise is a low-cost, safe and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for two weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-HT) synthesis using the tryptophan hydroxylase inhibitor PCPA prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor AMPT had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-HIAA), decreased expression of the serotonin transporter (SERT), and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Lastly, PNI-induced increased in inflammatory cytokines, TNF-α and IL-1β, in the brainstem was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.

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The fucogalactan from Agaricus bisporus (EFP-Ab) obtained on aqueous extraction followed by purification had M(w) 37.1 × 10(4)g mol(-1) relative to a (1→6)-linked α-D-Galp main-chain partially methylated at HO-3, and partially substituted at O-2 by nonreducing end-units of α-L-Fucp or β-d-Galp. EFP-Ab also inhibited significantly the neurogenic and inflammatory phases of formalin-induced licking, however, the antinociceptive effect was more pronounced against the inflammatory phase with ID(50) of 36.0 (25.8-50.3)mg kg(-1). In addition, EFP-Ab decreased the lethality induced by CLP. Its administration reduced the late mortality rate by 40%, prevented neutrophil accumulation in lungs and markedly decreased iNOS and COX-2 protein expression by ileum cells. These data show for the first time that EFP-Ab has significant anti-sepsis, antinociceptive and anti-inflammatory actions, which seems to be related to the decreased iNOS and COX-2 expression. Collectively, the present results demonstrate that EFP-Ab could constitute an attractive molecule of interest for the development of new drugs.

Medicinal health benefits uses of edible as well as non-edible mushrooms have been long recognized. The pharmacological potential of mushrooms, especially antitumor, immunostimulatory and anti-inflammatory activities has been documented. Wild ectomycorrhizal mushroom, Lactarius rufus had the anti-inflammatory and antinociceptive potential of their polysaccharides evaluated using the formalin model. Two structurally different (1→3),(1→6)-linked β-D-glucans were isolated from fruiting bodies. Soluble (FSHW) β-D-glucan 1-30 mg kg(-1) produced potent inhibition of inflammatory pain caused by formalin when compared with the insoluble one (IHW), suggesting that solubility and/or branching degree could alter the activity of β-glucans. Their structures were determined using mono- and bi-dimensional NMR spectroscopy, methylation analysis, and controlled Smith degradation. They were β-D-glucans, with a main chain of (1→3)-linked Glcp residues, substituted at O-6 by single-unit Glcp side chains (IHW), on average to every fourth residue of the backbone, or by mono- and few oligosaccharide side chains for soluble β-glucan.

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The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10-100mg/kg, i.p.) with ID(50) of 12.4 (8.5-18.1)mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E(2) (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100mg/kg, i.p.) and camphor (7.6 mg/kg,s.c.) in 43±10% and 57±8%, respectively. Myricitrin (30-100mg/kg, i.p.) and amiloride (100mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID(50) of 22.0 (16.1-30.0)mg/kg and inhibition of 71±6% and 64±5%, respectively. Moreover, myricitrin (10-30 mg/kg, i.p.) and ruthenium red (3mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 μmol/paw i.pl.) with the mean ID(50) of 2.4 (1.5-3.7)mg/kg and inhibition of 95±3% and 51±7%, respectively. In addition, myricitrin administration (30 and 100mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs.

Inosine is an endogenous nucleoside that has anti-inflammatory and antinociceptive properties. Inosine is a metabolite of adenosine, and some of its actions suggest the involvement of adenosine A1 receptors (A1Rs). The purpose of this study was to better understand mechanisms of inosine-induced antinociception by investigating the role of A1Rs and purine metabolism inhibitors. Inosine antinociception was evaluated using the formalin test in mice. An A1R-selective antagonist (DPCPX), A1R knockout mice (gene deletion) and mice with A1R reduced expression (antisense oligonucleotides) were used to assess the role of A1Rs in the antinociceptive action of inosine. Binding assays were performed to compare the affinity of inosine and adenosine for A1Rs. Finally, the role of adenosine and inosine breakdown was assessed using deoxycoformycin (DCF) and forodesine (FDS) as enzymatic inhibitors of adenosine deaminase and purine nucleoside phosphorylase, respectively. Inosine induced antinociception in the formalin test when given by systemic, spinal and peripheral routes. Systemically, inosine exhibited a potency similar to adenosine, and its effects were inhibited by DPCPX. Inosine did not induce antinociception in A1R knockout mice or in mice with reduced A1R expression. In binding studies, inosine bound to A1Rs with an affinity similar to adenosine. DCF had no effect on inosine actions. FDS augmented the antinociceptive effect of a low systemic dose of inosine and, at a higher dose, induced antinociception by itself. Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor.

A fucomannogalactan (FMG-Am) and a (1→3), (1→6)-linked β-D-glucan (βGLC-Am) were isolated from Amanita muscaria fruiting bodies. These compounds' structures were determined using mono- and bi-dimensional NMR spectroscopy, methylation analysis, and controlled Smith degradation. FMG-Am was shown to be a heterogalactan formed by a (1→6)-linked α-D-galactopyranosyl main chain partially substituted at O-2 mainly by α-L-fucopyranose and a minor proportion of β-D-mannopyranose non-reducing end units. βGLC-Am was identified as a (1→3)-linked β-D-glucan partially substituted at O-6 by mono- and a few oligosaccharide side chains, which was confirmed after controlled Smith degradation. Both the homo- and heteropolysaccharide were evaluated for their anti-inflammatory and antinociceptive potential, and they produced potent inhibition of inflammatory pain, specifically, 91±8% (30 mg kg(-1)) and 88±7% (10 mg kg(-1)), respectively.