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The increased pain sensitivity following reduced sleep may be related to changes in cortical processing of nociceptive stimuli. Expectations shape pain perception and can inhibit (placebo) or enhance (nocebo) pain. Sleep restriction appears to enhance placebo responses; however, whether sleep restriction also affects nocebo responses remains unknown. The aim of the present study was to determine whether sleep restriction facilitates nocebo-induced changes in pain and pain-evoked cortical potentials.
Learn More >Pituitary adenylate cyclase-activating polypeptide (PACAP) is found in two functional isoforms, namely PACAP38 and PACAP27. The migraine-inducing properties of PACAP38 are well studied. However, it is not known whether the lesser-known and under-studied protein isoform, PACAP27, can also induce migraine attacks. Here, we studied the effect of human PACAP27 infusion on induction of migraine in a provocation model.
Learn More >Itch stimuli are detected by specialized primary afferents, which convey the signal to the spinal cord, but how itch transmission is regulated is still incompletely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y2 receptor system on scratch behavior. The inhibitory Y2 receptor is expressed on mouse primary afferents and intrathecal administration of the Y2 agonist peptide YY (PYY)3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal pre-administration of the Y2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by α-methyl-5HT, SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to co-express itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT: The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y2 receptor. The Y2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b and interlekin 31 receptors.
Learn More >Mind-body therapies (MBTs) are emerging as potential tools for addressing the opioid crisis. Knowing whether mind-body therapies may benefit patients treated with opioids for acute, procedural, and chronic pain conditions may be useful for prescribers, payers, policy makers, and patients.
Learn More >Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. : CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. : Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. : For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.
Learn More >Pain is common in many different disorders and leads to a significant reduction in quality of life in the affected patients. Current treatment options are limited and often result in insufficient pain relief, partly due to the incomplete understanding of the underlying pathophysiological mechanisms. The identification of these pathomechanisms is therefore a central object of current research. There are also a number of rare pain diseases, that are generally little known and often undiagnosed, but whose correct diagnosis and examination can help to improve the management of pain disorders in general. In some of these unusual pain disorders like sodium-channelopathies or sensory modulation disorder the underlying pathophysiological mechanisms have only recently been unravelled. These mechanisms might serve as pharmacological targets that may also play a role in subgroups of other, more common pain diseases. In other unusual pain disorders, the identification of pathomechanisms has already led to the development of new drugs. A completely new therapeutic approach, the gene silencing, can even stop progression in hereditary transthyretin amyloidosis and porphyria, ie in pain diseases that would otherwise be rapidly fatal if left untreated. Thus, pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.
Learn More >Chronic tear deficiency enhances the excitability of corneal cold-sensitive nerves that detect ocular dryness, which can lead to discomfort in patients with dry eye disease (DED). However, changes in corneal nerve excitations through the polymodal nociceptor "transient receptor potential vanilloid 1" (TRPV1) and the potential link between this receptor and symptoms of DED remain unclear. In this study, we examined the firing properties of corneal cold-sensitive nerves expressing TRPV1 and possible contributions of chronic tear deficiency to corneal nerve excitability by TRPV1 activation. The bilateral excision of lacrimal glands in guinea pigs decreased the tear volume and increased the frequency of spontaneous eyeblinks 1-4 weeks after surgery. An analysis of the firing properties of the cold-sensitive nerves was performed by single-unit recordings of corneal preparations 4 weeks after surgery in both the sham-operated and gland-excised groups. Perfusion of the TRPV1 agonist, capsaicin (1 μM), transiently increased the firing frequency in approximately 46-48% of the cold-sensitive nerves characterized by low-background activity and high threshold (LB-HT) cold thermoreceptors in both groups. Gland excision significantly decreased the latency of capsaicin-induced firing in cold-sensitive nerves; however, its magnitude was unchanged. Calcium imaging of cultured trigeminal ganglion neurons from both groups showed that intracellular calcium elevation of corneal neurons induced by a low concentration of capsaicin (0.03 μM) was significantly larger in the gland excision group, regardless of responsiveness to cold. An immunohistochemical study of the trigeminal ganglion revealed that gland excision significantly increased the proportion of corneal neurons enclosed by glial fibrillary acidic protein (GFAP)-immunopositive satellite glial cells. Topical application of the TRPV1 antagonist, A784168 (30 μM), on the ocular surface attenuated eye-blink frequency after gland excision. Furthermore, gland excision enhanced blink behavior induced by a low concentration of capsaicin (0.1 μM). These results suggest that chronic tear deficiency sensitizes the TRPV1-mediated response in the corneal LB-HT cold thermoreceptors and cold-insensitive polymodal nociceptors, which may be linked to dry eye discomfort and hyperalgesia resulting from nociceptive stimuli in aqueous-deficient dry eyes.
Learn More >The potential use of cannabis and cannabinoid products for the treatment of low-back pain is an important area for investigation. As one of the leading reasons to visit a primary care provider, low-back pain results in a significant burden of disease in both the United States' economic and health care systems. Given the current opioid epidemic, it is important to seek novel analgesics and understand their efficacy for myriad pain conditions, including low-back pain. A systematic review was performed using multiple online databases to assess the association of cannabis use and low-back pain in the literature. A total of 124 articles were produced via our search methods, 73 abstracts in total were screened, 16 articles underwent full-text review, and 6 articles were included in qualitative synthesis. This systematic literature review reveals a lack of primary research investigating cannabis as a potential treatment of low-back pain and highlights the need for further investigation with well-designed clinical trials. There remain substantial political and legal barriers to performing such research. Although there is a considerable body of work on the usage of cannabinoid products for many medical conditions, including the treatment of chronic pain, more directed clinical research into their utility as an analgesic for low-back pain and related symptoms needs to be addressed.
Learn More >Pain has been associated with structural changes of the brain. However, evidence regarding white matter changes in response to acute pain protocols is still scarce. In the present study, we assess the existence of differences in brain white matter related to pain intensity reported by patients undergoing surgical removal of a mandibular impacted third molar using diffusion tensor imaging (DTI) analysis. 30 participants reported their subjective pain using a visual analog scale at three postsurgical stages: under anesthesia, in pain, and after the administration of an analgesic. The diffusion data were acquired prior to surgery. DTI analysis yielded significant positive associations of fractional anisotropy in white matter areas related to pain processing (corticospinal tract, corona radiata, corpus callosum) with the differences in pain between the three postsurgery stages. Extent and location of these associations depended on the magnitude of the subjective pain differences. Tractography analysis indicated that some pain-tract associations are significant only when pain stage is involved in the contrast (posterior corona radiata), while others (middle cerebellar peduncle, pontine crossing) are only when anesthesia is involved in the contrast. The association of white matter fractional anisotropy and connectivity, measured before the pain stages, with subjective pain depends on the magnitude of the differences in pain scores.
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