Accepted

Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N=95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain.

To evaluate the effectiveness of physiotherapy interventions on peripheral neuropathic pain (pNeP) due to any underlying cause.

To assess the effectiveness of mind-body (MB) exercise interventions provided by physical therapists for reducing pain and disability in people with low back pain (LBP).

Kinins are endogenous peptides that belong to the kallikrein-kinin system, extensively studied for over a century. Their essential role in multiple physiological and pathological processes is demonstrated by activating two transmembrane G-protein-coupled receptors, the kinin B and B receptors. Attention is mainly given to the pathological role of kinins in pain transduction mechanisms. In the past years, a wide range of preclinical studies has amounted to the literature reinforcing the need for an updated review about the participation of kinins and their receptors in pain disorders. Here, we performed an extensive literature search since 2004, describing the historical progress and the current understanding of the kinin receptors' participation and its potential therapeutic in several acute and chronic painful conditions. These include inflammatory (mainly arthritis), neuropathic (caused by different aetiologies, such as cancer, multiple sclerosis, antineoplastic toxicity and diabetes) and nociplastic (mainly fibromyalgia) pain. Moreover, we highlighted the pharmacological actions and possible clinical applications of the kinin B and B receptor antagonists, kallikrein inhibitors or kallikrein-kinin system signalling pathways-target molecules in these different painful conditions. Notably, recent findings sought to elucidate mechanisms for guiding new and better drug design targeting kinin B and B receptors to treat a disease diversity. Since the kinin B receptor antagonist, Icatibant, is clinically used and well-tolerated by patients with hereditary angioedema gives us hope kinin receptors antagonists could be more robustly tested for a possible clinical application in the treatment of pathological pains, which present limited pharmacology management.

Cognitive behavioral therapy for chronic pain (CBT-CP) is an evidence-based treatment for improving functioning and pain intensity for people with chronic pain with extensive evidence of effectiveness. However, there has been relatively little investigation of the factors associated with successful implementation and uptake of CBT-CP, particularly clinician and system level factors. This formative evaluation examined barriers and facilitators to the successful implementation and uptake of CBT-CP from the perspective of CBT-CP clinicians and referring primary care clinicians.

The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology.

Psoriatic arthritis (PsA) is a chronic, immune-mediated, spondyloarthropathy characterised by musculoskeletal signs and symptoms with associated joint pain and tenderness. The average worldwide PsA prevalence is 133/100,000, while in the Italian population is 90-420/100,000. Traditionally, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs have been used in the treatment of PsA. However, for those patients who are not adequately controlled with conventional therapies, the new biologics compounds represent a valid option. Biologic therapies have been shown to be more effective but also more expensive than conventional systemic treatments. Based on the CHRONOS study, the economic analyses presented in this paper aim to assess the annualised direct costs and the cost-per-responder of biologics in a real-world context assuming the Italian National Health System perspective.

In low back pain (LBP), primary care and secondary prevention of recurrent and persistent LBP are not always successful. Enhanced understanding of neural mechanisms of sensorimotor processing and pain modulation in patients with acute LBP is mandatory. This explorative fMRI study investigated sensorimotor processing due to mechanosensory stimulation of the lumbar spine. We studied 19 adult patients with acute LBP (< 4 weeks of an acute episode) and 23 healthy controls. On a numeric rating scale, patients reported moderate mean pain intensity of 4.5 out of 10, while LBP-associated disability indicated mild mean disability. The event-related fMRI analysis yielded no between-group differences. However, the computation of functional connectivity resulted in adaptive changes in networks involved in sensorimotor processing in the patient group: Connectivity strength was decreased in the salience and cerebellar networks but increased in the limbic and parahippocampal networks. Timewise, these results indicate that early connectivity changes might reflect adaptive physiological processes in an episode of acute LBP. These findings raise intriguing questions regarding their role in pain persistence and recurrences of LBP, particularly concerning the multiple consequences of acute LBP pain. Advanced understanding of neural mechanisms of processing non-painful mechanosensations in LBP may also improve therapeutic approaches.

The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (- 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential.

The ventrolateral periaqueductal gray (vlPAG) collaborates with the dorsal raphe (DR) in pain regulation and emotional response. However, the roles of vlPAG and DR γ-aminobutyric acid (GABA)-ergic neurons in regulating nociception and anxiety are contradictory and poorly understood. Here, we observed that pharmacogenetic co-activation of vlPAG and DR GABAergic (vlPAG-DR) neurons enhanced sensitivity to mechanical stimulation and promoted anxiety-like behavior in naïve mice. Simultaneous inhibition of vlPAG-DR neurons showed adaptive anti-nociception and anti-anxiety effects on mice with inflammatory pain. Notably, vlPAG and DR neurons exhibited opposing effects on the sensitivity to mechanical stimulation in both naïve state and inflammatory pain. In contrast to the role of vlPAG neurons in pain processing, chemogenetic inhibition and chronic ablation of DR neurons remarkably promoted nociception while selectively activating DR neurons ameliorated inflammatory pain. Additionally, utilizing optogenetic technology, we observed that the pronociceptive effect arising from DR neuronal inhibition was reversed by the systemic administration of morphine. Our results collectively provide new insights into the modulation of pain and anxiety by specific midbrain GABAergic subpopulations, which may provide a basis for cell type-targeted or subregion-targeted therapies for pain management.