Neurobiology of Pain最新文献

The cholecystokinin receptor system, specifically cholecystokinin 2 receptor (CCK2R) is a historic target for pain management that has shown limited success. However, new approaches to target CCK2R have incited fresh enthusiasm for this target. In this mini-review, we discuss what is known about CCK2R in peripheral and central circuits under naïve physiological conditions and under conditions of chronic pain, the interactions of CCK2Rs with opioids and briefly, recent efforts to develop new treatments targeting CCK2R for chronic pain.

Recent studies suggested that epigenetic mechanisms, including DNA methylation, may be involved in migraine pathogenesis. The calcitonin gene-related peptide (CGRP), encoded by calcitonin gene-related peptide 1 (CALCA) gene, plays a key role in the disease. The aim of the study was to evaluate DNA methylation of CALCA gene in patients with episodic migraine. 22 patients with episodic migraine (F/M 15/7, mean age 39.7 ± 13.4 years) and 20 controls (F/M 12/8, mean age 40.5 ± 14.8 years) were recruited. Genomic DNA was extracted from peripheral blood. Cytosine-to-thymine conversion was obtained with sodium bisulfite. The methylation pattern of two CpG islands in the promoter region of CALCA gene was analyzed. No difference of methylation of the 30 CpG sites at the distal region of CALCA promoter was observed between migraineurs and controls. Interestingly, in patients with episodic migraine the methylation level was lower in 2 CpG sites at the proximal promoter region (CpG −1461, p = 0.037, and −1415, p = 0.035, respectively). Furthermore, DNA methylation level at different CpG sites correlates with several clinical characteristics of the disease, as age at onset, presence of nausea/vomiting, depression and anxiety (p < 0.05). In conclusion, we found that DNA methylation profile in two CpG sites at the proximal promoter region of CALCA is lower in migraineurs when compared to controls. Intriguingly, the −1415 hypomethylated unit is located at the CREB binding site, a nuclear transcription factor. In addition, we found a correlation between the level of CALCA methylation and several clinical features of migraine. Further studies with larger sample size are needed to confirm these results.

Treatment with anti-neoplastic agents can lead to the development of chemotherapy induced peripheral neuropathy (CIPN), which is long lasting and often refractory to treatment. This neuropathic pain develops along dermatomes innervated by peripheral nerves with cell bodies located in the dorsal root ganglia (DRG). The voltage-gated sodium channel NaV1.7 is expressed at high levels in peripheral nerve tissues and has been implicated in the development of CIPN. Efforts to develop novel analgesics directly inhibiting NaV1.7 have been unsuccessful, and our group has pioneered an alternative approach based on indirect modulation of channel trafficking by the accessory protein collapsin response mediator protein 2 (CRMP2). We have recently reported a small molecule, compound 194, that inhibits CRMP2 SUMOylation by the E2 SUMO-conjugating enzyme Ubc9 (Cai et al. , Sci. Transl. Med. 2021 13(6 1 9):eabh1314). Compound 194 is a potent and selective inhibitor of NaV1.7 currents in DRG neurons and reverses mechanical allodynia in models of surgical, inflammatory, and neuropathic pain, including spared nerve injury and paclitaxelinduced peripheral neuropathy. Here we report that, in addition to its reported effects in rats, 194 also reduces mechanical allodynia in male CD-1 mice treated with platinumcomplex agent oxaliplatin. Importantly, treatment with 194 prevented the development of mechanical allodynia when co-administered with oxaliplatin. No effects were observed on the body weight of animals treated with oxaliplatin or 194 throughout the study period. These findings support the notion that 194 is a robust inhibitor of CIPN that reduces established neuropathic pain and prevents the emergence of neuropathic pain during treatment with multiple anti-neoplastic agents in both mice and rats.

Migraine is a leading cause of disability among the adult population and is a significant burden on the economies of the world. Studies into the underlying causes of migraine have spanned centuries but its underlying mechanisms are still not fully understood. In recent years, accumulating evidence implicates that microbiota-mediated gut-brain crosstalk may contribute to the pathogenesis of migraine. This review provides a brief account of the history of migraine theories and summarizes the recent studies showing how gut microbiota is involved in the pathophysiology of migraine. Future research perspectives for better understanding the role of the gut microbiota in migraine are also discussed.

Chronic pain arising from peripheral nerve injuries represents a significant clinical challenge because even the most efficacious anticonvulsant drug treatments are limited by their side effects profile. We investigated pain behavior, changes in axonal signal conduction and excitability of trigeminal neurons, and expression of voltage-gated sodium channels (NaVs) in the infraorbital nerve and trigeminal ganglion (TG) after infraorbital nerve entrapment (IoNE). Compared to Sham, IoNE rats had increased A- and C-fiber compound action potentials (CAPs) and Aδ component of A-CAP area from fibers innervating the vibrissal pad. After IoNE, A- and C-fiber CAPs were more sensitive to blockade by tetrodotoxin (TTX), and those fibers that were TTX-resistant were more sensitive to blockade by the NaV1.8 selective blocker, A-803467. Although NaV1.7 blocker, ICA-121431 alone, did not affect Aδ-fiber signal propagation, cumulative application with A-803467 and 4,9-anhydro-TTX significantly reduced the Aδ-fiber CAP in IoNE rats. In patch clamp recordings from small- and medium-sized TG neurons, IoNE resulted in reduced action potential (AP) depolarizing current threshold, hyperpolarized AP voltage threshold, increased AP duration, and a more depolarized membrane potential. While the transcripts of most NaVs were reduced in the ipsilateral TG after IoNE, NaV1.3, NaV1.7, and NaV1.8 mRNAs, and NaV1.8 protein, were significantly increased in the nerve. Altogether, our data suggest that axonal redistribution of NaV1.8, and to a lesser extent NaV1.3, and NaV1.7 contributes to enhanced nociceptive signal propagation in peripheral nerve after IoNE.

Background

Episodic migraine is considered to be cyclic in nature, triggered by the hypothalamus. To assess the natural trajectory of intrinsic networks over an entire migraine cycle, we designed a longitudinal intra-individual study using functional magnetic resonance imaging (fMRI).

Methods

Intrinsic network connectivity was assessed for 12 migraineurs in 82 sessions including spontaneous, untriggered headache attacks and follow-up recordings towards the next attack.

Results

We found cyclic changes in the visual, auditory, and somatosensory networks, in limbic networks (e.g. thalamo-insular, parahippocampal), and in the salience network (anterior insula and dorsal anterior cingulate cortex). Connectivity changes also extended to further cortical networks, such as the central executive network, the default mode network, as well as subcortical networks. Almost all of these network connectivity changes followed the trajectory of a linear increase over the pain-free interval that peaked immediately prior to the headache, and “dropped” to the baseline level during the headache. These network alterations are associated with a number of cortical functions that may explain the variety of ictal and pre-ictal physiological and psychological migraine symptoms.

Conclusion

Our results suggest that migraine disease is associated with widespread cyclic alterations of intrinsic networks that develop before the headache is initiated, i.e. during the interictal and premonitory phase. The increasing magnitude of connectivity within these networks towards the next attack may reflect an increasing effort to maintain network integrity.

In excess of 300 million surgical procedures are undertaken worldwide each year. Despite recognition of the prevalence of postoperative pain, and improvements in pain management techniques, poorly controlled postoperative pain remains a major unresolved challenge globally. An estimated 71% and 51% of patients experience moderate to severe pain after surgery in in-patient and outpatient settings, respectively. Inadequately controlled pain after surgery is associated with significant perioperative morbidity including myocardial infarction and pulmonary complications.

As many as 20–56% of patients develop chronic pain after commonly performed procedures such as hernia repair, hysterectomy, and thoracotomy. Traditional analgesics and interventions are often ineffective or partially effective in the treatment of postoperative pain, resulting in a chronic pain condition with related socio-economic impacts and reduced quality of life for the patient. Such chronic pain which occurs after surgery is referred to as Persistent Post-Surgical Pain (PPSP). The complex ecosystem that is the gastrointestinal microbiota (including bacteria, fungi, viruses, phage) plays essential roles in the maintenance of the healthy state of the host. A disruption to the balance of this microbiome has been implicated not only in gastrointestinal disease but also neurological disorders including chronic pain. The influence of the gut microbiome is well documented in the context of visceral pain from the gastrointestinal tract while a greater understanding is emerging of the impact on inflammatory pain and neuropathic pain (both of which can occur during the perioperative period). The gut microbiome is an essential source for driving immune maturation and maintaining appropriate immune response. Given that inflammatory processes have been implicated in postoperative pain, aberrant microbiome profiles may play a role in the development of this type of pain. Furthermore, the microorganisms in our gut produce metabolites, neurotransmitters, and neuromodulators which interact with their receptors to regulate peripheral and central sensitisation associated with chronic pain. Microbiota-derived mediators can also regulate neuroinflammation, which is associated with activation of microglia as well as infiltration by immune cells, known to modulate the development and maintenance of central sensitisation. Moreover, risk factors for developing postoperative pain include anxiety, depression, and increased stress response. These central nervous system-related disorders have been associated with an altered gut microbiome and microbiome targeted intervention studies indicate improvements. Females are more likely to suffer from postoperative pain. As gonadal hormones are associated with a differential microbiome and pre-clinical studies show that male microbiome confers protection from inflammatory pain, it is possible that the composition of the microbiome and its by-products co