A critical period in the supraspinal control of pain: opioid-dependent changes in brainstem rostroventral medulla function in preadolescence.

We have previously shown that the balance of electrically evoked descending brainstem control of spinal nociceptive reflexes undergoes a switch from excitation to inhibition in preadolescent rats. Here we show that the same developmental switch occurs when μ-opioid receptor agonists are microinjected into the rostroventral medulla (RVM). Microinjections of the μ-opioid receptor agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) into the RVM of lightly anaesthetised adult rats produced a dose-dependent decrease in mechanical nociceptive hindlimb reflex electromyographic activity. However, in preadolescent (postnatal day 21 [P21]) rats, the same doses of DAMGO produced reflex facilitation. RVM microinjection of δ-opioid receptor or GABA(A) receptor agonists, on the other hand, caused reflex depression at both ages. The μ-opioid receptor-mediated descending facilitation is tonically active in naive preadolescent rats, as microinjection of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) into the RVM at this age decreases spinal nociceptive reflexes while having no effect in adults. To test whether tonic opioid central activity is required for the preadolescent switch in RVM descending control, naloxone hydrochloride was delivered continuously from subcutaneous osmotic mini-pumps for 7-day periods, at various postnatal stages. Blockade of tonic opioidergic activity from P21 to P28, but not at earlier or later ages, prevented the normal development of descending RVM inhibitory control of spinal nociceptive reflexes. Enhancing opioidergic activity with chronic morphine over P7 to P14 accelerated this development. These results show that descending facilitation of spinal nociception in young animals is mediated by μ-opioid receptor pathways in the RVM. Furthermore, the developmental transition from RVM descending facilitation to inhibition of pain is determined by activity in central opioid networks at a critical period of periadolescence

Expression of Ankrd2 in fast and slow muscles and its response to stretch are consistent with a role in slow muscle function.

Item does not contain fulltextIn striated muscle, the structural genes associated with muscle fiber phenotype determination as well as muscle mass accretion are regulated largely by mechanical stimuli. Passive stretch of skeletal muscle stimulates muscle growth/hypertrophy and an increased expression of slow muscle genes. We previously identified Ankyrin repeat-domain protein (Ankrd2) as a novel transcript expressed in fast tibialis anterior muscles after 7 days of passive stretch immobilization in vivo. Here, we test the hypothesis that the expression of Ankrd2 in stretched fast muscle is associated with the stretch-induced expression of slow muscle phenotype rather than the hypertrophic response. Our results show that, in 4- and 7-day stretched tibialis anterior muscle, the expression of Ankrd2 mRNA and protein was significantly upregulated (P > 0.001). However, in fast muscles of kyphoscoliotic mutant mice, which lack the hypertrophic response to overload but have a slower muscle phenotype than wild-type, Ankrd2 expression was significantly upregulated. The distribution pattern of Ankrd2 in fast and slow muscle is also in accord with their slow fiber composition. Furthermore, it was markedly downregulated in denervated rat soleus muscle, which produces a pronounced shift toward the fast muscle phenotype. Using a sensitive proteomics approach (Ciphergen Technology), we observed that Ankrd2 protein was undetectable in soleus after 4 wk of denervation. We suggest that Ankrd2, which is also a titin binding protein, is a stretch-response gene associated with slow muscle function and that it is part of a separate mechanotransduction system to the one that regulates muscle mass

Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly-rectifying potassium channel activity

Hippocampal synaptic plasticity disruption by amyloid-β (Aβ) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G-protein-gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G-protein-coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ1-42 . In vitro electrophysiological recordings from slices showed that Aβ1-42 alters synaptic plasticity by switching high-frequency stimulation (HFS) induced long-term potentiation (LTP) to long-term depression (LTD), which led to in vivo hippocampal-dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS-induced LTP and habituation memory from Aβ1-42 action. Moreover, when GirK channels were specifically blocked by Tertiapin-Q, their activation with ML297 failed to rescue LTP from the HFS-dependent LTD induced by Aβ1-42 . On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aβ-mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS-induced LTP into LTD.Spanish Ministry of Economy and Competitivity MINECO-FEDER, Grant (BFU2014-56164-P and BFU2017-82494-P)Fundación Tatiana Pérez de Guzmán el BuenoUniversity of Castilla la Mancha5.372 JCR (2020) Q1, 78/295 Biochemistry & Molecular Biology1.75 SJR (2020) Q1, 69/438 BiochemistryNo data IDR 2020UE

Peripheral Administration of Translation Inhibitors Reverses Increased Hyperalgesia in a Model of Chronic Pain in the Rat

Chronic pain is extremely difficult to manage, in part due to lack of progress in reversing the underlying pathophysiology. Since translation of mRNAs in the peripheral terminal of the nociceptor plays a role in the transition from acute to chronic pain, we tested the hypothesis that transient inhibition of translation in the peripheral terminal of the nociceptor could reverse hyperalgesic priming, a model of transition from acute to chronic pain. We report that injection of translation inhibitors, rapamycin and cordycepin, which inhibit translation by different mechanisms, at the peripheral terminal of the primed nociceptor, produce reversal of priming, in the rat, that outlasted the duration of action of these drugs to prevent the development of priming. These data support the suggestion that interruption of translation in the nociceptor can reverse a preclinical model of at least one form of chronic pain