Systemic and intra-amygdala administrations of midazolam reverse anxiety-like behavior induced by cohabiting with a cagemate in chronic pain condition

The affective component of pain may be shared among conspecifics through emotional contagion, a form of empathic expression. In this sense, reverberation of negative emotions could generate distress behavioral responses, such as pathological anxiety. Evidences reported that amygdala and its benzodiazepine receptors are involved in perception of pain in others. However, relatively little is known about the neural processes underlying emotional contagion induced by pain observation. In the present study, we investigated the effects of midazolam, an allosteric GABAergic receptor agonist, in anxiety-like behaviors induced by cohabitation with cagemate submitted to sciatic nerve constriction. For this purpose, we administrated systemic (0.5, 1.0 and 2.0 mg/kg) and intra-amygdala midazolam injections (3.0 and 30.0 nmol) in observer cagemates before elevated plus-maze (EPM) evaluation. We found that mice subjected to nerve constriction and their observer cagemates increased anxiety-like behavior in the EPM. Further, systemically (1.0 and 2.0 mg/kg) and intra-amygdala administration of midazolam (3.0 and 30 nmol) reverse this anxiogenic effect. Collectively, these results suggest that social interaction with a cagemate under chronic pain produces anxiety-like responses that could be blocked through midazolam application.

Altered Hippocampal Functional Connectivity Is Closely Related to Pain and Catastrophic Thinking Habits in Patients With Postherpetic Neuralgia

Postherpetic neuralgia (PHN) is a chronic pain condition after a cure of herpes zoster. Patients with PHN often suffer from physical pain and psychological distress. We investigated the relationship between functional alternations in the brains of patients with PHN and their clinical manifestations using resting-state fMRI. We acquired resting-state fMRI data from 17 patients with PHN and matched healthy controls. We performed seed-based functional connectivity (FC) analysis and statistical comparisons in FC. We also performed correlation analysis between FC strengths and clinical scores about pain intensity, anxiety, depression and pain catastrophizing. In FC analysis, brain regions in the salience, default mode, sensorimotor and reward network were set as seeds. FC between the medial prefrontal cortex (mPFC) and hippocampus increased in PHN group. In contrast, FC between the hippocampus and primary somatosensory cortex (SI) decreased in PHN group. Furthermore, the SI-hippocampus FC was negatively correlated with pain intensity and the mPFC-hippocampus FC was positively correlated with pain catastrophizing tendency. Our findings indicate that the hippocampus is related to pain perception and catastrophic thinking habits in patients with PHN. Functional alteration of the hippocampus may have a major role in the development and maintenance of chronic pain condition in patients with PHN.

Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

The subgenual anterior cingulate cortex (sgACC) is a key node of the descending antinociceptive system with sex differences in its functional connectivity (FC). We previously reported that, in a male-prevalent chronic pain condition, sgACC FC is abnormal in women but not in men. This raises the possibility that, within a sex, sgACC FC may be either protective or represent a vulnerability to develop a sex-dominant chronic pain condition. The aim of this study was to characterize sgACC FC in a female-dominant chronic pain condition, carpal tunnel syndrome (CTS), to investigate whether sgACC abnormalities are a common feature in women with chronic pain or unique to individuals with pain conditions that are more prevalent in the opposite sex. We used fMRI to determine the resting state FC of the sgACC in healthy controls (HCs, n = 25, 18 women; 7 men) and people with CTS before (n = 25, 18 women; 7 men) and after (n = 17, 13 women; 4 men) successful surgical treatment. We found reduced sgACC FC with the medial pre-frontal cortex (mPFC) and temporal lobe in CTS compared with HCs. The group-level sgACC-mPFC FC abnormality was driven by men with CTS, while women with CTS did not have sgACC FC abnormalities compared with healthy women. We also found that age and sex influenced sgACC FC in both CTS and HCs, with women showing greater FC with bilateral frontal poles and men showing greater FC with the parietal operculum. After surgery, there was reduced sgACC FC with the orbitofrontal cortex, striatum, and premotor areas and increased FC with the posterior insula and precuneus compared with pre-op scans. Abnormally reduced sgACC-mPFC FC in men but not women with a female-prevalent chronic pain condition suggests pain-related sgACC abnormalities may not be specific to women but rather to individuals who develop chronic pain conditions that are more dominant in the opposite sex. Our data suggest the sgACC plays a role in chronic pain in a sex-specific manner, and its communication with other regions of the dynamic pain connectome undergoes plasticity following pain-relieving treatment, supporting it as a potential therapeutic target for neuromodulation in chronic pain.

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

Vulvodynia—It Is Time to Accept a New Understanding from a Neurobiological Perspective

Vulvodynia is one the most common causes of pain during sexual intercourse in premenopausal women. The burden of vulvodynia in a woman’s life can be devastating due to its consequences in the couple’s sexuality and intimacy, in activities of daily living, and psychological well-being. In recent decades, there has been considerable progress in the understanding of vulvar pain. The most significant change has been the differentiation of vulvar pain secondary to pathology or disease from vulvodynia. However, although it is currently proposed that vulvodynia should be considered as a primary chronic pain condition and, therefore, without an obvious identifiable cause, it is still believed that different inflammatory, genetic, hormonal, muscular factors, etc. may be involved in its development. Advances in pain neuroscience and the central sensitization paradigm have led to a new approach to vulvodynia from a neurobiological perspective. It is proposed that vulvodynia should be understood as complex pain without relevant nociception. Different clinical identifiers of vulvodynia are presented from a neurobiological and psychosocial perspective. In this case, strategies to modulate altered central pain processing is necessary, changing the patient’s erroneous cognitions about their pain, and also reducing fear avoidance-behaviors and the disability of the patient.

Women with Fibromyalgia Prefer Resistance Exercise with Heavy Loads—A Randomized Crossover Pilot Study

Fibromyalgia (FM) is a chronic pain condition associated with impaired muscle strength and exercise-induced pain. Physical exercise has been highlighted, by international clinical guidelines and stakeholders, as an essential component of rehabilitation in FM. Exposure to pain during exercise is generally correlated with elevated lactate levels and, additionally, is one known reason for persons with FM to avoid physical exercise and activity. A crossover design was used to test and evaluate an approach consisting of resistance exercise with heavy loads and a low number of repetitions among ten women with FM. The participants were consecutively recruited to test and perform exercise with two different resistance levels (A = light/moderate load, and B = heavy load) in a randomized crossover trial using an AB/BA setting. Results showed that the heavy load exercise session was experienced as more positive than the light/moderate load exercise session and that lower lactate levels followed exercise with heavier weight loads. This is promising and indicates that the approach of heavy weight loads and accustomed repetitions is accepted in FM and has the potential to attenuate hesitation to exercise due to exercise-induced pain. However, these effects need to be further investigated in more extensive studies.

Neuropathic corneal pain and dry eye: a continuum of nociception

Throughout the body, damage to peripheral nerves normally involved in nociception may produce a constellation of symptoms—including irritation, itchiness and pain. The neurobiological processes involved in corneal symptoms of dry eye (DE) and neuropathic corneal pain (NCP) have not been clearly considered in terms of nociceptive processing. The conventional underlying presumption is that a labelled line principle is responsible; that these distinct perceptions are hard coded by primary afferent inputs to the central nervous system. This presumption oversimplifies the neurobiological mechanisms underlying somatosensory perception. The labelled line perspective that DE represents a chronic pain condition does not make intuitive sense: how can an eye condition that is not painful in most cases be considered a pain condition? Does not chronic pain by definition require pain to be present? On the other hand, NCP, a term that clearly denotes a painful condition, has historically seemed to resonate with clinical significance. Both DE and NCP can share similar features, yet their differentiation is not always clear. As is often the case, clinical terms arise from different disciplines, with DE evolving from ophthalmological findings and NCP inspired by pain neurophysiology. This review evaluates the current definition of these terms, the rationale for their overlap and how the neurophysiology of itch impacts our understanding of these conditions as a continuum of the same disease. Despite the complexity of nociceptive physiology, an understanding of these mechanisms will allow us a more precise therapeutic approach.

The NLRP3 inflammasome: an emerging therapeutic target for chronic pain

Chronic pain affects the life quality of the suffering patients and posts heavy problems to the health care system. Conventional medications are usually insufficient for chronic pain management and oftentimes results in many adverse effects. The NLRP3 inflammasome controls the processing of proinflammatory cytokine interleukin 1β (IL-1β) and is implicated in a variety of disease conditions. Recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain condition and contributes to pathogenesis of chronic pain. This review provides an up-to-date summary of the recent findings of the involvement of NLRP3 inflammasome in chronic pain and discussed the expression and regulation of NLRP3 inflammasome-related signaling components in chronic pain conditions. This review also summarized the successful therapeutic approaches that target against NLRP3 inflammasome for chronic pain treatment.

Intravenous cannula used for continuous intraoral mandibular nerve block in trigeminal neuralgia

Trigeminal neuralgia is a chronic pain condition affecting one or more distributions of the trigeminal nerve. Patients with this condition experience short, sharp, shooting pain attacks, which can progress to longer, more frequent durations. The pain is often difficult to control. We report of a man who was admitted with severe neuralgia of the third division of the trigeminal nerve. Talking and any oral intake triggered a severe agonising pain. The latter made the regular oral intake of analgesia challenging. The pain was temporarily controlled with frequent local anaesthesia (LA). Dental core trainees were performing regular inferior alveolar nerve blocks which significantly improved patients’ condition allowing him to communicate and have oral intake. Subsequently, a catheter was placed allowing for a continuous anaesthesia. The connecting tube of the cannula was then used by nursing staff to administer LA providing pain relief without the need of repeated intraoral injections.