Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity

<p>Abstract</p> <p>Background</p> <p>Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin.</p> <p>Results</p> <p>We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced <it>c-fos </it>expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21–39 min) and late (40–60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception.</p> <p>Conclusion</p> <p>The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.</p

Evidence and perceptions of rainfall change in Malawi: Do maize cultivar choices enhance climate change adaptation in sub-Saharan Africa?

Getting farmers to adopt new cultivars with greater tolerance for coping with climatic extremes and variability is considered as one way of adapting agricultural production to climate change. However, for successful adaptation to occur, an accurate recognition and understanding of the climate signal by key stakeholders (farmers, seed suppliers and agricultural extension services) is an essential precursor. This paper presents evidence based on fieldwork with smallholder maize producers and national seed network stakeholders in Malawi from 2010 to 2011, assessing understandings of rainfall changes and decision-making about maize cultivar choices. Our findings show that preferences for short-season maize cultivars are increasing based on perceptions that season lengths are growing shorter due to climate change and the assumption that growing shorter-season crops represents a good strategy for adapting to drought. However, meteorological records for the two study areas present no evidence for shortening seasons (or any significant change to rainfall characteristics), suggesting that short-season cultivars may not be the most suitable adaptation option for these areas. This demonstrates the dangers of oversimplified climate information in guiding changes in farmer decision-making about cultivar choice