Pannexin 1 (Panx1) is involved in the spinal central sensitization process in rats with neuropathic pain, but its interaction with well-known, pain-related, ligand-dependent receptors, such as NMDA receptors (NMDAR) and P2X7 purinoceptors (P2X7R), remains largely unexplored. Here, we studied whether NMDAR- and P2X7R-dependent nociceptive signaling in neuropathic rats require the activation of Panx1 channels to generate spinal central sensitization, as assessed by behavioral (mechanical hyperalgesia) and electrophysiological (C-reflex wind-up potentiation) indexes. Administration of either a selective NMDAR agonist i.t. (NMDA, 2 mM) or a P2X7R agonist (BzATP, 150 μM) significantly increased both the mechanical hyperalgesia and the C-reflex wind-up potentiation, effects that were rapidly reversed (minutes) by i.t. administration of a selective pannexin 1 antagonist (10panx peptide, 300 μM), with the scores even reaching values of rats without neuropathy. Accordingly, 300 μM 10panx completely prevented the effects of NMDA and BzATP administered 1 h later, on mechanical hyperalgesia and C-reflex wind-up potentiation. Confocal immunofluorescence imaging revealed coexpression of Panx1 with NeuN protein in intrinsic dorsal horn neurons of neuropathic rats. The results indicate that both NMDAR- and P2X7R-mediated increases in mechanical hyperalgesia and C-reflex wind-up potentiation require neuronal Panx1 channel activation to initiate and maintain nociceptive signaling in neuropathic rats.

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α₁-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α₁-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α₁-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α₁-adrenoceptor density in whole hypothalamus and the expression levels of α_1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α₁-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α_1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

The link between metabolism and reproduction is well-known. Both undernutrition and obesity affect the reproductive system. Metabolic status influences reproductive physiology by regulating gonadotropin secretion and affecting reproductive organs through hormonal signals. On the other hand, the autonomic nervous system controls follicle development and ovulation in the female reproductive system. This system is regulated by hypothalamic areas associated with metabolism as the Arcuate nuclei (ARC) and paraventricular nuclei (PVN). Metabolic signals, such as nutrients and hormones, acting on the hypothalamus may play a crucial role in modulating sympathetic innervation of the ovary and other reproductive organs. Some of these hormones are leptin, insulin, and GLP-1 that act directly in the hypothalamus to activate the sympathetic nervous system. In this minireview, we propose that leptin could be an important regulator of sympathetic innervation in reproductive tissues. Leptin may affect the density or activity of sympathetic nerves, thereby affecting reproductive function. We also speculate that other hormones such as insulin and GLP-1 may activate sympathetic nerves to the ovary. Additionally, we explore how early-onset obesity can cause lasting changes in the autonomic control of metabolic and reproductive organs, especially in the ovary. This suggests that the hyperactivation of sympathetic nerves in adulthood, due to metabolic programming, could be a possible cause of reproductive and metabolic disorders, such as polycystic ovary syndrome.

The exposure to sympathetic stress during the entire period of gestation (4 °C/3 h/day) strongly affects the postnatal reproductive performance of the first generation of female offspring and their fertility capacity. The aim of this work was to determine whether this exposure to sympathetic stress affects the reproductive capacity of the next three generations of female offspring as adults. Adult female Sprague–Dawley rats were mated with males of proven fertility. We studied the reproductive capacity of the second, third, and fourth generations of female offspring (the percentage of pregnancy and the number and weight of female offspring). The estrus cycle activity of the progenies was studied, and a morphological analysis of the ovaries was carried out to study the follicular population. The second generation had a lower number of pups per litter and a 20% decrease in fertile capacity. The estrus cycle activity of the third generation decreased even more, and they had a 50% decrease in their fertile capacity, and their ovaries presented polycystic morphology. The fourth generation however, recovered their reproductive capacity but not the amount of newborns pups. Most probably, the chronic intrauterine exposure to the sympathetic stress programs the female gonads to be stressed in a stressful environment; since the fourth generation was the first born with no direct exposure to stress during development, it opens studies on intrauterine factors affecting early follicular development.

A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.

Neuropathic pain reduces GABA and glycine receptor (GlyR)-mediated activity in spinal and supraspinal regions associated with pain processing. Interleukin-1β (IL-1β) alters Central Amygdala (CeA) excitability by reducing glycinergic inhibition in a mechanism that involves the auxiliary β-subunit of GlyR (βGlyR), which is highly expressed in this region. However, GlyR activity and its modulation by IL-1β in supraspinal brain regions under neuropathic pain have not been studied. We performed chronic constriction injury (CCI) of the sciatic nerve in male Sprague Dawley rats, a procedure that induces hind paw plantar hyperalgesia and neuropathic pain. Ten days later, the rats were euthanized, and their brains were sliced. Glycinergic spontaneous inhibitory currents (sIPSCs) were recorded in the CeA slices. The sIPSCs from CeA neurons of CCI animals show a bimodal amplitude distribution, different from the normal distribution in Sham animals, with small and large amplitudes of similar decay constants. The perfusion of IL-1β (10 ng/mL) in these slices reduced the amplitudes within the first five minutes, with a pronounced effect on the largest amplitudes. Our data support a possible role for CeA GlyRs in pain processing and in the neuroimmune modulation of pain perception.