Cumulative effects of multiple pain sites in youth with chronic pain.

BACKGROUND: The experience of persistent pain in multiple locations is common in youth. Based on current literature, youth with multiple pain sites (MPS) are at risk of experiencing poorer emotional outcomes and a spread of symptoms into late adolescence and adulthood. Little is known regarding the association between MPS with physical and school functioning domains, particularly after initiation of multidisciplinary pain treatment. Therefore, the objective of this study was to examine the association of MPS with disability and school functioning among youth with chronic pain. METHODS: A total of 195 patients with chronic pain, aged 8-17, and their parents completed measures assessing patient distress and functioning at a multidisciplinary pain clinic evaluation and at 4-month follow-up. RESULTS: At evaluation, 63% of patients presented with MPS; 25% reporting MPS endorsed pain in five or more locations. When controlling for relevant demographic and emotional distress factors, MPS were associated with lower school functioning at evaluation with a persistent trend at follow-up. Although MPS were not a significant predictor of pain-related disability at evaluation, it emerged as significant at follow-up. CONCLUSIONS: Potentially due to the MPS load and the inverse effects that such a pain state has on function, such patients may be at risk for poorer health and school-related outcomes. The mechanisms influencing these relationships appear to extend beyond psychological/emotional factors and warrant further investigation in order to aid in our understanding of youth with MPS. SIGNIFICANCE: Youth with MPS may be at risk for experiencing poorer physical and school functioning in comparison with single-site peers, despite treatment initiation. Further research is warranted to inform assessment and treatment approaches for this subgroup of patients.

Tunable Kondo physics in a carbon nanotube double quantum dot.

We investigate a tunable two-impurity Kondo system in a strongly correlated carbon nanotube double quantum dot, accessing the full range of charge regimes. In the regime where both dots contain an unpaired electron, the system approaches the two-impurity Kondo model. At zero magnetic field the interdot coupling disrupts the Kondo physics and a local singlet state arises, but we are able to tune the crossover to a Kondo screened phase by application of a magnetic field. All results show good agreement with a numerical renormalization group study of the device.

Effect of MDL 105,212, a nonpeptide NK-1/NK-2 receptor antagonist in an allergic guinea pig model.

MDL 105,212 has been identified as a potent, nonpeptide NK-1 and NK-2 receptor antagonist that inhibits effects of substance P and neurokinin A in vitro and in vivo (Kudlacz et al., 1996). In the present study, the compound inhibited capsaicin-induced respiratory effects after p.o. administration (5-50 mg/kg) to conscious guinea pigs; nearly complete inhibition of dyspnea and cough was observed 1 hr after 50 mg/kg p.o., and efficacy persisted for approximately 11 hr. MDL 105,212 reduced pulmonary insufflation pressure and microvascular leakage in ovalbumin-sensitized animals in response to antigen-challenge relative to vehicle-treated animals. Attenuation of early-phase allergic responses may result from MDL 105,212 inhibition of antigen-induced histamine release from sensitized guinea pig lung observed in vitro. Airway hyperresponsiveness to methacholine occurred 24 hr after antigen-challenge in ovalbuminsensitized guinea pigs; this effect was inhibited by pretreatment with MDL 105,212 (50 mg/kg p.o.) 1 hr before ovalbumin exposure without affecting increased bronchoalveolar lavage eosinophil numbers. These data suggest that sensory neuropeptides play a role in some aspects of allergic airway responses and that tachykinin receptor antagonists may be useful in treatment of atopic respiratory diseases.

In vitro and in vivo characterization of MDL 105,212A, a nonpeptide NK-1/NK-2 tachykinin receptor antagonist.

We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.

Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists.

Tachykinins, in particular neurokinin A and substance P, produce a number of airway effects which may contribute to respiratory diseases such as asthma. We examined the ability of aerosolized substance P, neurokinin A or capsaicin to produce respiratory alterations in conscious guinea pigs using modified whole body plethysmography. Substance P-mediated dyspnea and significant respiratory events were inhibited by the NK1 receptor antagonist, CP-96,345. Neurokinin A-mediated respiratory effects were ablated by the NK2 receptor antagonists: MEN 10207, MDL 29,913 and SR 48,968, the latter being the most potent. The peptide-based antagonist, MEN 10207, produced respiratory effects itself suggesting partial agonist activity. The cyclic hexapeptide, MDL 29,913, relaxed airway smooth muscle via mechanisms other than tachykinin antagonism. NK2 but not NK1 receptor antagonists were able to delay the onset of capsaicin-induced dyspnea, although alone they did not usually (in approximately 10% of the animals) eliminate the response. However, when NK2 receptor antagonists were combined with CP-96,345, the incidence of dyspnea induced by capsaicin decreased significantly (40%) suggesting that both tachykinins contribute to dyspnea in this system.

Methylacetylenic putrescine (MAP), an inhibitor of polyamine biosynthesis, prevents the development of collagen-induced arthritis.

The objective of the present investigation was to examine the effects of an irreversible inhibitor of ornithine decarboxylase (2R,5R)-6-heptyne-2,5,diamine (methylacetylenic putrescine, MAP) on experimentally induced arthritis in mice. MAP (0.5-0.05%) was administered in drinking water to DBA/1 mice immunized with native chick type II collagen (CII). The development of arthritis was inhibited only in those mice receiving 0.5% MAP; lower doses were ineffective. Putrescine and spermidine levels were decreased and spermine levels were increased in spleen and lymph node cells from drug-treated mice compared to control arthritic mice. Furthermore, when control mice were developing arthritis, serum anti-CII antibody levels were lower in the MAP-treated group. MAP inhibited antibody production early in the immune response to CII; there was an association between inhibition of antibody production and inhibition of the development of arthritis. When MAP was discontinued, the nonarthritic, drug-treated mice did not develop the disease. Late administration of MAP (beginning 19 days after CII immunization) did not affect the incidence or the severity of the arthritis. Cyclophosphamide treatment begun at the same time significantly inhibited the development of the disease. In vitro T cell responses to denatured type II collagen (dCII) in untreated and MAP-treated mice were examined 14 days after immunization with CII. This is a time of peak T cell responsiveness in untreated animals. MAP treatment had no effect on the T cell response to dCII. These results indicate that MAP can prevent the development of CII-induced arthritis, possibly by inhibiting the autoantibody response. Therefore, inhibitors of polyamine biosynthesis deserve further investigation as potential immunosuppressive agents.