Age-dependent sensitization of cutaneous nociceptors during developmental inflammation.

BACKGROUND: It is well-documented that neonates can experience pain after injury. However, the contribution of individual populations of sensory neurons to neonatal pain is not clearly understood. Here we characterized the functional response properties and neurochemical phenotypes of single primary afferents after injection of carrageenan into the hairy hindpaw skin using a neonatal ex vivo recording preparation. RESULTS: During normal development, we found that individual afferent response properties are generally unaltered. However, at the time period in which some sensory neurons switch their neurotrophic factor responsiveness, we observe a functional switch in slowly conducting, broad spiking fibers ("C"-fiber nociceptors) from mechanically sensitive and thermally insensitive (CM) to polymodal (CPM). Cutaneous inflammation induced prior to this switch (postnatal day 7) specifically altered mechanical and heat responsiveness, and heat thresholds in fast conducting, broad spiking ("A"-fiber) afferents. Furthermore, hairy skin inflammation at P7 transiently delayed the functional shift from CM to CPM. Conversely, induction of cutaneous inflammation after the functional switch (at P14) caused an increase in mechanical and thermal responsiveness exclusively in the CM and CPM neurons. Immunocytochemical analysis showed that inflammation at either time point induced TRPV1 expression in normally non-TRPV1 expressing CPMs. Realtime PCR and western blotting analyses revealed that specific receptors/channels involved in sensory transduction were differentially altered in the DRGs depending on whether inflammation was induced prior to or after the functional changes in afferent prevalence. CONCLUSION: These data suggest that the mechanisms of neonatal pain development may be generated by different afferent subtypes and receptors/channels in an age-related manner.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation.

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRG). However, specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. Growth hormone modulates homeostasis and tissue repair after injury, but how GH affects nociception in neonates is not known. To determine whether GH played a role in modulating sensory neuron function and hyperresponsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-DRG-spinal cord preparation. Results show that inflammation of the hairy hind paw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated through an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that after GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRG.

Sizing ocean giants: patterns of intraspecific size variation in marine megafauna.

What are the greatest sizes that the largest marine megafauna obtain? This is a simple question with a difficult and complex answer. Many of the largest-sized species occur in the world's oceans. For many of these, rarity, remoteness, and quite simply the logistics of measuring these giants has made obtaining accurate size measurements difficult. Inaccurate reports of maximum sizes run rampant through the scientific literature and popular media. Moreover, how intraspecific variation in the body sizes of these animals relates to sex, population structure, the environment, and interactions with humans remains underappreciated. Here, we review and analyze body size for 25 ocean giants ranging across the animal kingdom. For each taxon we document body size for the largest known marine species of several clades. We also analyze intraspecific variation and identify the largest known individuals for each species. Where data allows, we analyze spatial and temporal intraspecific size variation. We also provide allometric scaling equations between different size measurements as resources to other researchers. In some cases, the lack of data prevents us from fully examining these topics and instead we specifically highlight these deficiencies and the barriers that exist for data collection. Overall, we found considerable variability in intraspecific size distributions from strongly left- to strongly right-skewed. We provide several allometric equations that allow for estimation of total lengths and weights from more easily obtained measurements. In several cases, we also quantify considerable geographic variation and decreases in size likely attributed to humans.