Sarret, P. | Search bioRxiv

bioRxiv2018

Neurotensin and Dynorphin Bi-Directionally Modulates CeA Inhibition of oval BNST Neurons in Male Mice

Neuropeptides are often co-expressed in neurons but their neurophysiological effects are commonly studied individually. Multiple neuropeptides may therefore be simultaneously released to coordinate proper neural circuit function. Here, we triggered the release of endogenous neuropeptides in brain slices from male mice to better understand the modulation of central amygdala (CeA) inhibitory inputs onto oval (ov) BNST neurons. We found that locally-released neurotensin (NT) and dynorphin (Dyn) antagonistically regulated CeA inhibitory inputs onto ovBNST neurons. NT and Dyn respectively increased and decreased CeA-to-ovBNST inhibitory inputs through NT receptor 1 (NTR1) and kappa opioid receptor (KOR). Additionally, NT and Dyn mRNAs were highly co-localized in ovBNST neurons suggesting that they may be released from the same cells. Together, we showed that NT and Dyn are key modulators of CeA inputs to ovBNST, paving the way to determine whether different conditions or states can alter the neuropeptidergic regulation of this particular brain circuit.

neuroscience↗

bioRxiv2016

Analgesic effects of neurotensin agonists in a rat bone cancer pain model

Bone metastases are a source of intractable pain, resistant to conventional opioid and non-opioid analgesics. The neurotensin system represents a potential pathway toward bone cancer pain (BCP) relieve via the inhibition of its receptors NTS1 and NTS2. Capitalizing on our recent results using neurotensin analogs in inflammatory and neuropathic pain models, we here show, for the first time, a potential role for neurotensin receptors agonists in the treatment of BCP. The novel non-selective agonist JMV-2009 (300 g/kg) reversed mechanical allodynia in our rodent BCP model at both early and late stages of the disease. The NTS2-selective agonist JMV-431 (90 g/kg), in addition to anti-allodynia, also had an effect on weight bearing deficits. In parallel, we tested proven analgesics from several classes to put the effect of neurotensin analogs in perspective and found that morphine (3 mg/kg), tramadol (15 mg/kg) and amitriptyline (10 mg/kg) had mild effects on BCP while the cannabinoid nabilone (1 mg/kg) significantly reversed both allodynia and weight bearing deficits. Taken together, our results affirm the potential of the modulation of the neurotensin system for the development of new analgesics for the treatment of bone cancer pain.

pharmacology and toxicology↗