BackgroundSomatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis.Methods and FindingsSelective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and −6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor α (TNFα) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis.ConclusionsThese data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFα-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.

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2-Chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine, ATR)is a toxicologically important and widely used herbicide. Recent studies have shown that it can elicit neurological, immunological, developmental, and biochemical alterations in several model organisms, including in mice. Because disposition data in mice are lacking, we evaluated ATR's metabolism and tissue dosimetry after single oral exposures (5-250 mg/kg) in C57BL/6 mice using liquid chromatography/mass spectrometry (Ross and Filipov, 2006). ATR was metabolized and cleared rapidly; didealkyl ATR (DACT) was the major metabolite detected in urine, plasma, and tissues. Plasma ATR peaked at 1 h postdosing and rapidly declined, whereas DACT peaked at 2 h and slowly declined. Most ATR and metabolite residues were excreted within the first 24 h. However, substantial amounts of DACT were still present in 25-to 48-h and 49-to 72-h urine. ATR reached maximal brain levels (0.06-1.5 M) at 4 h (5-125 mg/kg) and 1 h (250 mg/kg) after dosing, but levels quickly declined to <0.1 M by 12 h in all the groups. In contrast, strikingly high concentrations of DACT (1.5-50 M), which are comparable with liver DACT levels, were detectable in brain at 2 h. Brain DACT levels slowly declined, paralleling the kinetics of plasma DACT. Our findings suggest that in mice ATR is widely distributed and extensively metabolized and that DACT is a major metabolite detected in the brain at high levels and is ultimately excreted in urine. Our study provides a starting point for the establishment of models that link target tissue dose to biological effects caused by ATR and its in vivo metabolites.Atrazine (ATR) is a triazine herbicide that effectively inhibits photosynthesis in broadleaf weeds and grasses (Environmental Protection Agency, 2003). In the United States, ATR is applied on crops such as corn, sugarcane, pineapples, macadamia nuts, and sorghum, as well as on highway and railroad rights-of-way and on evergreen trees (Environmental Protection Agency, 2003). Several epidemiological studies have investigated the link between ATR exposure and adverse human health outcomes (Hoppin et al., 2002;MacLennan et al., 2002;De Roos et al., 2003;Hessel et al., 2004). However, the human data at present are equivocal. In some cases ATR exposure is associated with negative health outcomes, whereas in others it is not. One major drawback of virtually all the existing epidemiological studies is the fact that ATR exposure has not been precisely quantified or estimated. In this regard, exposure-only studies, i.e., studies where health outcomes have not been assessed, indicate that pesticide applicators and farmers during spraying are exposed to appreciable levels of ATR because detectable amounts of ATR and its metabolites are found in their saliva and urine (Hines et al., 2006). Moreover, a recent report indicated that not only ATR applicators but also their families are at risk of high level of ATR exposure (Curwin et al., 2007).Although data on health effects of ATR in humans ar...

Secondary mechanical allodynia resulting from a thermal stimulus (52.5 degrees C for 45s) is blocked by intrathecal (i.t.) pretreatment with calcium-permeable AMPA/KA receptor antagonists, but not NMDA receptor antagonists. Spinal sensitization is presumed to underlie thermal stimulus-evoked secondary mechanical allodynia. We investigated whether this spinal sensitization involves activation and phosphorylation of calcium-dependent protein kinases (PKA, PKC and CaMKIIalpha), and examined if the noxious stimulus increases phosphorylated AMPA GLUR1 (pGLUR1 Ser-845 and pGLUR1 Ser-831). Secondary mechanical allodynia after thermal stimulation was not altered by i.t. pretreatment with control vehicles (saline or 5% DMSO). Comparable allodynia was observed after pretreatment with a selective CaMKIIalpha inhibitor (17 and 34nmol KN-93). In marked contrast, pretreatment with either a PKA (10nmol H89) or PKC (30nmol chelerythrine) inhibitor blocked allodynia. Western immunoblot analyses supported behavioral findings and revealed a thermal stimulus-evoked increase in spinal phosphorylated PKA and PKC, but not CaMKIIalpha. There was no increase in any of the total protein kinases. Although thermal stimulation did not change either pGLUR1 Ser-845 or pGLUR1 Ser-831, it was associated with an increase in cytosolic total GLUR1. Pretreatment with a selective calcium-permeable AMPA/KA receptor antagonist (5nmol joro spider toxin), but not an NMDA receptor antagonist (25nmol d-2-amino-5-phosphonovalerate, AP-5), blocked thermal stimulus-evoked increases in phosphorylated PKA and PKC, in addition to increased cytosolic GLUR1. These findings indicate that spinal sensitization in the thermal stimulus model does not involve CaMKIIalpha activation or AMPA GLUR1 receptor phosphorylation, and differs from that occurring in NMDAr-dependent pain states.