Accepted

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome, namely "autoimmune autonomic dysfunction syndromes". Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.

Animal models of migraine have been widely used during the last decades to provide clues for understanding mechanisms underlying pathophysiology of migraine attacks and for developing specific therapeutic agents. They can be grouped into two main types: vascular and neurovascular. Trigemino-vascular system (TVS) is the most relevant efferent component and the mediators of its activity have been thoroughly studied along with some of the receptors involved to characterize anatomical and functional aspects of the system and to test efficacy and mechanisms of therapeutic agents. Neurovascular models are numerous. Plasma protein extravasation (PPE) model consists of measuring the amount of proteins leaking from vessels when TVS is either electrically or chemically stimulated and evaluating its blockade by systemically administered therapeutic agents of which specific receptors have also been identified. Activation of trigeminal nucleus caudalis (TNC) through meningeal stimulation of the superior sagittal sinus served to better understand the mechanisms of central nociceptive pathway. The cortical spreading depression (CSD) model has been used to activate the TVS through application of potassium chloride and evaluate Fos expression in the trigeminal nucleus caudalis (TNC). Finally, neurochemical, cerebrovascular, and nociceptive response to systemic or central administration of nitric oxide (NO) donors served to study central nociceptive pathway and autonomic response interaction. Transgenic mouse expressing human migraine mutations has been genetically engineered to provide an understanding of familial hemiplegic migraine (FHM). Animal models of migraine also served to better understand the role of hormones, genes, and environmental factors on migraine pathophysiology.

Transient receptor potential vanilloid-1 (TRPV1), activated by heat, acidic pH, endogenous vanilloids, and capsaicin, is essential for thermal hyperalgesia. Under inflammatory conditions, phosphorylation of TRPV1 by protein kinase C (PKC) can sensitize the channel and decrease the activation threshold. Src kinase also phosphorylates TRPV1, promoting channel trafficking to the plasma membrane. These post-translational modifications are important for several chronic pain conditions. This study presents a previously undescribed relationship between Src and PKC phosphorylation of TRPV1, influencing the thermal hypersensitivity associated with TRPV1 activation.

Allergic conjunctivitis is highly prevalent and affects up to one third of the general population. The current understanding of the pathophysiology and therapeutic strategies center around the type 2 inflammatory pathway. However, there is an increasing body of evidence that suggests neurogenic mechanisms also play a role in allergic inflammation, with a substantial proportion of allergic conjunctivitis patients experiencing both ocular itch and pain.

Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent.

Galcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated efficacy and good tolerability in patients with episodic migraine in previous phase 3 trials. We report results from the PERSIST study, which was designed to assess the efficacy and safety of galcanezumab in patients with episodic migraine from China, India, and Russia.