Neurokinin receptor mechanisms in forebrain medial septum modulate nociception in the formalin model of inflammatory pain

The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.

The Regulation Effect of α7nAChRs and M1AChRs on Inflammation and Immunity in Sepsis

The inflammatory storm in the early stage and immunosuppression in the late stage are responsible for the high mortality rates and multiple organ dysfunction in sepsis. In recent years, studies have found that the body’s cholinergic system can spontaneously and dynamically regulate inflammation and immunity in sepsis according to the needs of the body. Firstly, the vagus nerve senses and regulates local or systemic inflammation by means of the Cholinergic Anti-inflammatory Pathway (CAP) and activation of α7-nicotinic acetylcholine receptors (α7nAChRs); thus, α7nAChRs play important roles for the central nervous system (CNS) to modulate peripheral inflammation; secondly, the activation of muscarinic acetylcholine receptors 1 (M1AChRs) in the forebrain can affect the neurons of the Medullary Visceral Zone (MVZ), the core of CAP, to regulate systemic inflammation and immunity. Based on the critical role of these two cholinergic receptor systems in sepsis, it is necessary to collect and analyze the related findings in recent years to provide ideas for further research studies and clinical applications. By consulting the related literature, we draw some conclusions: MVZ is the primary center for the nervous system to regulate inflammation and immunity. It coordinates not only the sympathetic system and vagus system but also the autonomic nervous system and neuroendocrine system to regulate inflammation and immunity; α7nAChRs are widely expressed in immune cells, neurons, and muscle cells; the activation of α7nAChRs can suppress local and systemic inflammation; the expression of α7nAChRs represents the acute or chronic inflammatory state to a certain extent; M1AChRs are mainly expressed in the advanced centers of the brain and regulate systemic inflammation; neuroinflammation of the MVZ, hypothalamus, and forebrain induced by sepsis not only leads to their dysfunctions but also underlies the regulatory dysfunction on systemic inflammation and immunity. Correcting the neuroinflammation of these regulatory centers and adjusting the function of α7nAChRs and M1AChRs may be two key strategies for the treatment of sepsis in the future.

Ca2+ and Membrane Potential Transitions During Action Potentials Are Self-Similar to Each Other and to Variability of AP Firing Intervals Across the Broad Physiologic Range of AP Intervals During Autonomic Receptor Stimulation

Ca2+ and Vm transitions occurring throughout action potential (AP) cycles in sinoatrial nodal (SAN) cells are cues that (1) not only regulate activation states of molecules operating within criticality (Ca2+ domain) and limit-cycle (Vm domain) mechanisms of a coupled-clock system that underlies SAN cell automaticity, (2) but are also regulated by the activation states of the clock molecules they regulate. In other terms, these cues are both causes and effects of clock molecular activation (recursion). Recently, we demonstrated that Ca2+ and Vm transitions during AP cycles in single SAN cells isolated from mice, guinea pigs, rabbits, and humans are self-similar (obey a power law) and are also self-similar to trans-species AP firing intervals (APFIs) of these cells in vitro, to heart rate in vivo, and to body mass. Neurotransmitter stimulation of β-adrenergic receptor or cholinergic receptor–initiated signaling in SAN cells modulates their AP firing rate and rhythm by impacting on the degree to which SAN clocks couple to each other, creating the broad physiologic range of SAN cell mean APFIs and firing interval variabilities. Here we show that Ca2+ and Vm domain kinetic transitions (time to AP ignition in diastole and 90% AP recovery) occurring within given AP, the mean APFIs, and APFI variabilities within the time series of APs in 230 individual SAN cells are self-similar (obey power laws). In other terms, these long-range correlations inform on self-similar distributions of order among SAN cells across the entire broad physiologic range of SAN APFIs, regardless of whether autonomic receptors of these cells are stimulated or not and regardless of the type (adrenergic or cholinergic) of autonomic receptor stimulation. These long-range correlations among distributions of Ca2+ and Vm kinetic functions that regulate SAN cell clock coupling during each AP cycle in different individual, isolated SAN cells not in contact with each other. Our numerical model simulations further extended our perspectives to the molecular scale and demonstrated that many ion currents also behave self-similar across autonomic states. Thus, to ensure rapid flexibility of AP firing rates in response to different types and degrees of autonomic input, nature “did not reinvent molecular wheels within the coupled-clock system of pacemaker cells,” but differentially engaged or scaled the kinetics of gears that regulate the rate and rhythm at which the “wheels spin” in a given autonomic input context.

Screening for Copy Number Variations of the 15q13.3 Hotspot in CHRNA7 Gene and Expression in Patients with Migraines

Background: a migraine is a neurological disease. Copy number variation (CNV) is a phenomenon in which parts of the genome are repeated. We investigated the effects of the CNV and gene expression at the location 15q13.3 in the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, which we believe to be effective in the migraine clinic. Methods: we evaluated changes in CHRNA7 gene expression levels and CNV of 15q13.3 in patients with migraine (n = 102, with aura, n = 43; without aura, n = 59) according to healthy controls (n = 120) by q-PCR. The data obtained were analyzed against the reference telomerase reverse transcriptase (TERT) gene with the double copy number by standard curve analysis. Copy numbers were graded as a normal copy (2), gain (2>), and loss (<2). Results: we analyzed using the 2−ΔΔCT calculation method. The CHRNA7 gene was significantly downregulated in patients (p < 0.05). The analysis of CNV in the CHRNA7 gene was statistically significant in the patient group, according to healthy controls (p < 0.05). A decreased copy number indicates a dosage loss. However, no significant difference was observed among gain, normal, and loss copy numbers and expression values in patients (p > 0.05). The change in CNV was not associated with the downregulation of the CHRNA7 gene. Conclusion: Downregulation of the CHRNA7 gene may contribute to the formation of migraine by inactivation of the alpha-7 nicotinic receptor (α7nAChR). The association of CNV gains and losses with migraines will lead to better understanding of the molecular mechanisms and pathogenesis, to better define the disease, to be used as a treatment target.