TRP Channels as Molecular Targets to Relieve Cancer Pain

Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.

Sensory Neuron Expressed TRPC3 Mediates Acute and Chronic Itch

Background: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. However, the role of TRPC3 in acute and chronic itch is still not well defined. Methods: RNAscope in situ hybridization and immunohistochemical staining were performed on mouse trigeminal ganglion (TG) neurons. Fura-2 calcium imaging was used to characterize the function of TRPC3 in dissociated TG neurons. In native mice, the TRPC3 agonist and pruritogens were subcutaneously injected to the cheek and nape of the neck of mice, respectively. Site directed scratching and/or wiping behaviors were video recorded. Contact hypersensitivity (CHS) model was induced in mouse ears by topical application of SADBE or DNCB. Spontaneous scratching behaviors were recorded by video monitoring. Global and conditional Trpc3 knockout mice were employed to determine the contribution of TRPC3 to acute and chronic itch. The mRNA expression levels of Trpc3 and proinflammatory cytokines were assayed by quantitative real-time PCR. H&E. staining was used for the evaluation of the thickness of mouse ears. Flow cytometry was performed to assess immune cell infiltration in mouse ear tissues. Results: Among mouse TG neurons, RNAscope assay revealed that Trpc3 mRNA was predominantly expressed in nonpeptidergic small diameter neurons. Moreover, Trpc3 mRNA signal was present in the majority of itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch- and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of CHS, Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. Conclusions: These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

Enhanced sensory conduction in primary fibromyalgia: a case–control pilot study

Background This study aimed to test the changes in the conduction properties of peripheral nerves in patients with primary fibromyalgia (FM). Thirty patients with FM and sixteen healthy controls participated in this study. Visual analogue scale (VAS) for pain severity, pain duration, Widespread Pain Index (WPI), Symptom Severity (SS) scale, Hamilton depression rating scale, Taylor’s manifest anxiety scale, and Fibromyalgia Impact Questionnaire (FIQR) were used for measurement of psychiatric comorbidities and quality of life for each patient. Routine motor and sensory nerve conduction studies of both median, ulnar, common peroneal, posterior tibial, and sural nerves were measured for all study participants. Results We found statistically significant increase in Sensory Conduction Velocity (SCV), Sensory Nerve Action Potential (SNAP) amplitude, and decrease in Sensory Latency (SL) in patients with FM compared to controls. There were no significant changes in motor nerve conduction between patients and controls. Regression analysis showed a significant relation between WPI and both SCV and SL especially in nerves of upper limbs. However, no significant relation between SCV and SL and other presumed predictors including VAS for pain severity, pain duration, SS scale, FIQR, and psychiatric comorbidities. Patients with FM suffered more depression and anxiety than controls. Conclusions We found enhanced conductivity of the sensory rather than the motor nerves in patients with FM. To our knowledge, this is the first study to describe these sensory changes which may add further evidence of peripheral sensitization in patients with FM.

Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes

Endometriosis-associated pain and the mechanisms responsible for its initiation and persistence are complex and difficult to treat. Endometriosis-associated pain is experienced as dysmenorrhea, cyclical pain related to organ function including dysuria, dyschezia and dyspareunia, and persistent pelvic pain. Pain symptomatology correlates poorly with the extent of macroscopic disease. In addition to the local effects of disease, endometriosis-associated pain develops as a product of peripheral sensitization, central sensitization and cross sensitization. Endometriosis-associated pain is further contributed to by comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia and vulvodynia. This article will review endometriosis-associated pain, its mechanisms, and its comorbid pain syndromes with a view to aiding the clinician in navigating the literature and terminology of pain and pain syndromes. Limitations of our current understanding of endometriosis-associated pain will be acknowledged. Where possible, commonalities in pain mechanisms between endometriosis-associated pain and comorbid pain syndromes will be highlighted.

Chronic Pain in the Elderly: Mechanisms and Distinctive Features

Background: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with dementia and cognitive impairment or on the efficacy and tolerability of medications. In this review, we searched for evidence of specific pain mechanisms or modifications in pain signals processing either at the cellular level or in the central nervous system. Methods: Narrative review. Results: Investigation on pain sensitivity led to conflicting results, with some studies indicating a modest decrease in age-related pain sensitivity, while other researchers found a reduced pain threshold for pressure stimuli. Areas of the brain involved in pain perception and analgesia are susceptible to pathological changes such as gliosis and neuronal death and the effectiveness of descending pain inhibitory mechanisms, particularly their endogenous opioid component, also appears to deteriorate with advancing age. Hyperalgesia is more common at older age and recovery from peripheral nerve injury appears to be delayed. In addition, peripheral nociceptors may contribute minimally to pain sensation at either acute or chronic time points in aged populations. Conclusions: Elderly subjects appear to be more susceptible to prolonged pain development, and medications acting on peripheral sensitization are less efficient. Pathologic changes in the central nervous system are responsible for different pain processing and response to treatment. Specific guidelines focusing on specific pathophysiological changes in the elderly are needed to ensure adequate treatment of chronic pain conditions.

Role of Neuroimmune Crosstalk in Mediating the Anti-inflammatory and Analgesic Effects of Acupuncture on Inflammatory Pain

Inflammatory pain is caused by peripheral tissue injury and inflammation. Inflammation leads to peripheral sensitization, which may further cause central sensitization, resulting in chronic pain and progressive functional disability. Neuroimmune crosstalk plays an essential role in the development and maintenance of inflammatory pain. Studies in recent years have shown that acupuncture can exert anti-inflammatory and analgesic effects by regulating peripheral (i.e., involving local acupoints and inflamed regions) and central neuroimmune interactions. At the local acupoints, acupuncture can activate the TRPV1 and TRPV2 channels of mast cells, thereby promoting degranulation and the release of histamine, adenosine, and other immune mediators, which interact with receptors on nerve endings and initiate neuroimmune regulation. At sites of inflammation, acupuncture enables the recruitment of immune cells, causing the release of opioid peptides, while also exerting direct analgesic effects via nerve endings. Furthermore, acupuncture promotes the balance of immune cells and regulates the release of inflammatory factors, thereby reducing the stimulation of nociceptive receptors in peripheral organs. Acupuncture also alleviates peripheral neurogenic inflammation by inhibiting the release of substance P (SP) and calcitonin gene-related peptide from the dorsal root ganglia. At the central nervous system level, acupuncture inhibits the crosstalk between glial cells and neurons by inhibiting the p38 MAPK, ERK, and JNK signaling pathways and regulating the release of inflammatory mediators. It also reduces the excitability of the pain pathway by reducing the release of excitatory neurotransmitters and promoting the release of inhibitory neurotransmitters from neurons and glial cells. In conclusion, the regulation of neuroimmune crosstalk at the peripheral and central levels mediates the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain in an integrated manner. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of inflammatory diseases.

Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently, nociplastic pain has been introduced as a descriptor of the mechanism of pain, which is due to the disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring the participation of psychosocial and behavioral factors in central sensitization of diseases progressing into the development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

Assessment and Brain Training of Patients Experiencing Head and Facial Pain with a Distortion of Orofacial Somatorepresentation: A Narrative Review

The management of patients experiencing chronic orofacial pain is a great challenge, due to the complexity of chronic pain itself, combined with an increased peripheral sensitization in the craniofacial itself. Therefore, patients with orofacial pain may present a clear distortion of the somatorepresentation after some time. In this review, the authors develop a neurophysiological explanation of orofacial distortion, as well as propose assessment and treatment options, based on scarcely available scientific evidence and their own clinical experience. The assessments of facial somatosensory, cognitive-affective and motor dysfunctions are crucial to establish the most accurate treatment; the assessment tools are described in the article. Two-point discrimination, laterality recognition and emotion recognition are altered in patients with orofacial pain. Other sensorimotor assessment tools, such as motor acuity and auditory acuity, are also explained. Finally, the authors review their treatment proposals, based on the integration of brain training techniques and biobehavioral interventions. Somatosensory reintegration (tactile acuity training), facial emotion recognition, movement representation techniques, orofacial motor training and therapeutic patient education are explained in detail, and this may challenge new directions in rehabilitation and research.