Local Translation in Primary Afferent Fibers Regulates Nociception

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states

Maternal birthweight and outcome of twin pregnancy

The definitive version is available at www.blackwell-synergy.comThere is evidence from singletons that maternal birthweight is positively related to offspring gestational length and birthweight, and some evidence of an inverse relationship with preterm birth. Among twins very preterm birth is the major cause of neonatal mortality and of immediate and later morbidity, including neurodevelopmental impairment. We hypothesised that the relationship between maternal birthweight and gestational length would be more evident in twin than in singleton pregnancies, as there is more variation in gestation in the former. Among 131 singleton mothers carrying twins, there was weak evidence of a positive relationship between maternal birthweight and twin gestational length (+0.6 weeks [95% CI −0.05, +1.3] per kg increase in maternal birthweight, but stronger evidence among 56 of these who went into labour spontaneously (+1.9 weeks [+0.7, +3.1], P = 0.003 for interaction). In the latter group we estimated that the odds of very preterm birth (at <32 weeks) were reduced by 50% [95% CI 10%, 82%] per 250 g increase in maternal birthweight. In the whole cohort, and in this subgroup, maternal birthweight was strongly positively related to both twin offspring total birthweight and total placental weight. Our data, consistent with intergenerational programming of early development, suggest the possibility of a stronger and more clinically relevant association among twins than among singletons. Nevertheless, our sample size was modest and this finding needs to be confirmed in a larger cohort.Ruth Morley, Vivienne M. Moore, Terence Dwyer, Julie A. Owens, Mark P. Umstad and John B. Carli