Animal Studies

The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.

Prostaglandin E (PGE) is an important inflammatory mediator for the initiation and maintenance of inflammatory and neuropathic pain. The acute effect of PGE on sodium currents has been widely characterized in sensory neurons; however, the prolonged effect of PGE remains to be determined. Here, we performed patch clamp recordings to evaluate the acute and prolonged effects of PGE on sodium currents in trigeminal ganglionic (TG) neurons from male Sprague-Dawley rats. We found that 24-h treatment with PGE (10 μM) increased the peak sodium current density by approximately 31% in a voltage-dependent manner and shifted the activation curve in a hyperpolarized direction but did not affect steady-state inactivation. Furthermore, treatment with PGE for 24 h increased the current density of tetrodotoxin-sensitive (TTX-S) but not TTX-resistant (TTX-R) channels significantly. Interestingly, TTX-S current was increased mostly in medium-sized, but not in small-sized, neurons after 24 h of treatment with PGE. Moreover, the mRNA level of TTX-S Nav1.1 but not TTX-R Nav1.8 or Nav1.9 was significantly increased after 24 h of treatment with PGE In contrast, 5-min treatment with PGE (10 μM) increased the peak sodium current density by approximately 29% and increased TTX-R sodium currents, but not TTX-S currents, in both small- and medium-sized TG neurons. Our results presented a differential regulation of subtypes of sodium channels by acute and prolonged treatments of PGE, which may help to better understand the mechanism of PGE-mediated orofacial pain development.

Recent studies have shown that the incidence of chronic primary pain (CPP) including temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently reported that central sensitization and descending facilitation system contributed to the development of somatic pain hypersensitivity induced by orofacial inflammation combined with stress. The purpose of this study was to explore whether TMD caused by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and whether the cholecystokinin (CCK) receptor-mediated descending facilitation system promotes hypersensitivity through neuron-glia cell cascade signaling. UAC evoked thermal and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked at week 4 post UAC. The expression levels of CCK1 receptors, IL-18 and IL-18 receptors (IL-18R) were significantly up-regulated in the L4-L5 spinal dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent with neurons. These findings indicate that the signaling transduction between neurons and glia at the spinal cord level contributes to the descending pain facilitation through CCK1 receptors during the development of the comorbidity of TMD and FMS. Perspective: CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade, providing novel therapeutic targets for the clinical treatment of TMD and FMS comorbidities.

Our laboratory has recently shown that there is a decrease in neuronal complexity in head pain processing regions in mouse models of chronic migraine-associate pain and aura. Importantly, restoration of this neuronal complexity corresponds with anti-migraine effects of known and experimental pharmacotherapies. The objective of the current study was to expand this work and examine other brain regions involved with pain or emotional processing. We also investigated the generalizability of our findings by analyzing neuronal cytoarchitectural changes in a model of complex regional pain syndrome (CRPS), a peripheral pain disorder.

Inflammatory bowel disease (IBD) is a gastrointestinal disease characterized by diarrhea, rectal bleeding, abdominal pain, and weight loss. Recombinant probiotics producing specific proteins with IBD therapeutic potential are currently considered novel drug substitutes. In this study, a Bifidobacterium bifidum BGN4-SK strain was designed to produce the antioxidant enzymes streptococcal superoxide dismutase (SOD) and lactobacillus catalase (CAT), and a B. bifidum BGN4-pBESIL10 strain was proposed to generate an anti-inflammatory cytokine, human interleukin (IL)-10. In vitro and in vivo efficacy of these genetically modified Bifidobacterium strains were evaluated for colitis amelioration.

Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signalling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeA neurons) and project to the lateral parabrachial nucleus (LPBN), a brainstem region known for its critical role in distributing nociceptive and other aversive signals throughout the brain. In male Sprague-Dawley rats, we show that CeA-LPBN neurons are GABAergic and mostly express somatostatin. In anaesthetised rats, optogenetic stimulation of CeA-LPBN projections inhibited responses of LPBN neurons evoked by electrical activation of Aδ- and C-fibre primary afferents; this inhibition could be blocked by intra-LPBN application of the GABA receptor antagonist bicuculline. CeA-LPBN stimulation also dampened LPBN responses to noxious mechanical, thermal, and chemical stimuli. In behaving rats, optogenetic stimulation of CeA-LPBN projections attenuated nocifensive responses to mechanical pressure and radiant heat, disrupted the ability of a noxious shock to drive aversive learning, reduced the defensive behaviours of thigmotaxis and freezing, induced place preference, and promoted food consumption in sated rats. Thus, we suggest that CeA-LPBN projections mediate a form of analgesia that is accompanied by a shift towards the positive-appetitive pole of the emotional-motivational continuum. Since the affective state of pain patients strongly influences their prognosis, we envision that recruitment of this pathway in a clinical setting could potentially promote pain resilience and recovery.Pain and emotion interact on multiple levels of the nervous system. Both positive and negative emotion may have analgesic effects. However, while the neuronal mechanisms underlying "stress-induced analgesia" have been the focus of many studies, the neuronal substrates underlying analgesia accompanied by appetitive emotional-motivational states have received far less attention. The current study focuses on a subpopulation of amygdala neurons that form inhibitory synapses within the brainstem lateral parabrachial nucleus. We show that activation of these amygdalo-parabrachial projections inhibits pain processing, while also reducing behaviours related to negative affect and enhancing behaviours related to positive affect. We propose that recruitment of this pathway would benefit pain patients, many of whom suffer from psychological comorbidities such as anxiety and depression.

Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.