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Evidence indicates that over half of all people with HIV (PWH) will experience nonmalignant chronic pain throughout their lifetimes, with increasing prevalence as they age. Peripheral neuropathy resulting from the neurotoxic effects of HIV itself and the medications used to treat HIV were widely considered the primary cause of acute and chronic pain early on in the antiretroviral treatment era. However, recent studies suggest a predominance of non-neuropathic (e.g., musculoskeletal) pain in PWH with uncertain etiology. Chronic pain is often widespread in PWH, affecting multiple body locations. Additional research is needed to better understand contributors to chronic pain in PWH, which is likely to include biological (e.g., immune dysregulation), psychological (e.g., substance abuse) and social (e.g., stigma) factors.
Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the orthologous gene.
Cluster headache (CH) is clinically associated with considerable psychosocial burden. However, instruments to assess and characterize psychosocial factors in cluster headache more specifically are lacking. This study aimed to develop a self-report questionnaire, which assesses the broadest possible spectrum of psychosocial factors in cluster headache, the Cluster Headache Scales (CHS).
Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
Youth with functional abdominal pain disorders (FAPDs) may report high rates of trauma and/or posttraumatic stress disorder (PTSD), which could impact both physical and psychosocial functioning, in addition to psychosocial treatment response. The current study aimed to examine the rates of PTSD in a sample of 89 youth with FAPDs and examine the association between PTSD with physical and psychosocial functioning. The impact of PTSD on psychosocial treatment response in a subsample of youth with FAPDs was also explored. Participants were youth with FAPDs (ages 9-14) enrolled in a larger study examining the effect of a short-term pain and anxiety focused cognitive behavioral therapy (CBT) treatment (Aim to Decrease Anxiety and Pain Treatment (ADAPT)) for youth with FAPDs. Youth were administered a semi-structured diagnostic interview by a trained clinician to confirm the presence of psychological diagnoses, including PTSD. Measures of physical and psychosocial functioning were also completed. Results revealed a high rate of PTSD in youth with FAPDs with 12.4% meeting diagnostic criteria for the disorder. PTSD was associated with several indicators of increased psychosocial impairment and one indicator of physical impairment. Exploratory analyses revealed comorbid PTSD may impact response to a brief CBT intervention targeting pain and anxiety, but more rigorous controlled studies are needed.
Factors such as gender, ethnicity, and age affect pain processing in children and adolescents with chronic pain. Although obesity has been shown to affect pain processing in adults, almost nothing is known about pediatric populations. The aim of this pilot study was to explore whether obesity alters sensory processing in adolescents with chronic pain. Participants were recruited from a chronic pain clinic (Chronic Pain (CP), = 12 normal weight; Chronic Pain + Obesity (CPO), = 19 overweight/obesity) and from an obesity clinic (Obesity alone (O), = 14). The quantitative sensory testing protocol included assessments of thermal and mechanical pain thresholds and perceptual sensitization at two sites with little adiposity. The heat pain threshold at the hand was significantly higher in the CPO group than in either the CP or O groups. Mechanical pain threshold (foot) was significantly higher in the CPO group than the CP group. No differences were found on tests of perceptual sensitization. Correlations between experimental pain and clinical pain parameters were found for the CPO group, but not for the CP group. This preliminary study provides important lessons learned for subsequent, larger-scale studies of sensory processing for youth with co-occurring chronic pain and obesity.
In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, ~20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors (proenkephalin, prodynorphin, and proopiomelanocortin) by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides bind to all three of the opioid receptor types (mu, delta, kappa), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been utilized to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e. to excised tissue) or in vivo (in animals), using antagonists of specific opioid receptors to infer endogenous peptide activity, and using positron-emission tomography (PET) to detect a change in receptor availability, a sign of peptide release. While each of these approaches have weaknesses, certain observations have been consistent across modalities thereby adding to our current understanding of the function of endogenous opioids. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.
Quantitative sensory testing protocols for perceptions of pleasantness and unpleasantness based on the German Research Network on Neuropathic Pain protocol were recently introduced. However, there are no reliability studies yet published.
Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches.
Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents.