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Human fear conditioning research since Watson's case study on "Little Albert" has vastly evolved and its impact today is reaching far beyond phobic anxiety. This review focuses on how fear conditioning research, mainly using exteroceptive conditioned stimuli (CSs) and aversive, non-noxious stimuli as unconditioned stimuli (USs), has been extended and translated to chronic pain research. We describe the different pain-related fear conditioning paradigms using proprioceptive and interoceptive CSs and painful stimuli as USs that have been developed to study specific forms of pain-related fear (i.e. fear of movement, fear of touch, fear of visceral sensations, and fear of penetration) that are relevant for different chronic pain conditions (i.e. musculoskeletal pain, neuropathic pain, visceral pain, and genital pain). We present evidence that patients with chronic pain demonstrate impaired safety learning and excessive fear generalization; learning anomalies that have also been observed in anxiety disorders. Extinction-based protocols (exposure in vivo) have been developed to reduce pain-related fear and increase daily functioning in various chronic pain disorders. Finally, we outline some challenges and future directions to further our understanding of learning mechanisms underlying the development, persistence, and treatment of chronic pain disability.
Learn More >Increasing evidence suggests that activation of satellite glia cells (SGCs) in sensory ganglia play important roles in the development of neuropathic pain. The present study aimed to investigate the involvement of SGC activation in a novel model of motor nerve injury induced pain hypersensitivity. The neuropathic pain model was established by cervical 8 ventral root avulsion (C8VA). Glial fibrillary acidic protein (GFAP) was used as a marker of SGC activation. Unilateral C8VA resulted in mechanical allodynia, but not thermal hyperalgesia in bilateral paws. Expectedly, SGCs were robustly activated on as early as 1 day and persisted for at least 7 days in the ipsilateral and contralateral dorsal root ganglia (DRG) of C6, C7 and C8 after C8VA. Double immunofluorescence showed that almost all the activated SGCs enveloped neurofilament 200 (NF200) positive myelinated neurons in DRG. Local application of fluorocitrate (FC), a glial metabolism inhibitor, significantly decreased the number of activated SGCs and alleviated bilateral mechanical allodynia. These results suggest that SGC activation contributed to ipsilateral and mirror-image pain hypersensitivity after C8VA. Inhibition of SGC activation represented a promising therapeutic strategy for the management of neuropathic pain following brachial plexus root avulsion.
Learn More >Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. We investigated self-reported cold extremities as a marker for vascular dysfunction in migraine. Secondly, we hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency.
Learn More >Vulvodynia is a condition that occurs in 8-10% of women of all ages and is characterized by pain at the vulva that is present during sexual and/or non-sexual situations. Diagnosis is established through careful medical history and pelvic examination, including the cotton-swab test. The onset and maintenance of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression and childhood maltreatment as well as cognitive-affective, behavioural and interpersonal factors. Given the absence of empirically supported treatment guidelines, a stepwise approach of pelvic floor physical therapy and cognitive behavioural therapy as well as medical management is suggested, with surgery as the last option. Vulvodynia has a negative effect on the quality of life of women and their partners, and imposes a profound personal and societal economic burden. In addition, women with vulvodynia are more likely to report other chronic pain conditions, which further alters their quality of life. Future efforts should aim to increase girls', women's and healthcare professionals' education and awareness of vulvodynia, phenotype different subgroups of women based on biopsychosocial characteristics among more diverse samples, conduct longitudinal studies and improve clinical trial designs.
Learn More >Burning mouth syndrome is a chronic oral pain disorder that is characterized by a generalized or localized burning sensation without the presence of any specific mucosal lesions. It remains unclear, however, whether burning mouth syndrome is associated with the development of psychoneurological conditions among patients with the syndrome.
Learn More >Protease-activated receptor 2 (PAR2) has long been implicated in inflammatory and visceral pain, but the cellular basis of PAR2-evoked pain has not been delineated. While PAR2-evoked pain has been attributed to sensory neuron expression, RNA-sequencing experiments show ambiguous F2rl1 mRNA detection. Moreover, many pharmacological tools for PAR2 are nonspecific, acting also on the Mas-related GPCR family (Mrg) that are highly enriched in sensory neurons. We sought to bring clarity to the cellular basis of PAR2 pain. We developed a PAR2 conditional mutant mouse and specifically deleted PAR2 in all sensory neurons using the PirtCre mouse line. Our behavioral findings show that PAR2 agonist-evoked mechanical hyperalgesia and facial grimacing, but not thermal hyperalgesia, is dependent on PAR2 expression in sensory neurons that project to the hind paw in male and female mice. F2rl1 mRNA is expressed in a discrete population (~4%) of mostly small-diameter sensory neurons that co-express the Nppb and IL31ra genes. This cell population has been implicated in itch, but our work shows that PAR2 activation in these cells causes clear pain-related behaviors from the skin. Our findings show that a discreet population of DRG sensory neurons mediate PAR2-evoked pain.
Learn More >Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P -(C5) , of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P -(C5) disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P -(C5) administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P -(C5) as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein-protein interaction domains.
Learn More >Sleep disorders and circadian dysregulation appear to be associated with primary headache disorders.
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