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Infants spending extended time in the neonatal intensive care unit are at greater risk of developing a variety of mental health problems later in life, possibly due to exposure to painful/stressful events. We used a rodent model of inflammatory neonatal pain to explore effects on fear conditioning, somatosensory function and maternal behavior. Hindpaw injections of 2% λ-carrageenan on postnatal days 1 and 4 produced an attenuation in conditioned freezing during the postweaning period, similar to our previous work with acute pain, but did not cause lasting impacts on contextual freezing nor somatosensory function. Additionally, we assessed maternal behavior to observe dam-pup interactions during the neonatal period. Results showed dams of litters which experienced pain spent similar amounts of time with pups as undisturbed controls. However, the specific behaviors differed per condition. Dams of pain litters exhibited less time licking/grooming, but more time nursing than controls. These results suggest changes in maternal care following pain could be a contributing factor underlying the long-term effects of neonatal trauma. Furthermore, our laboratory has previously shown acute, but not inflammatory pain, disrupted conditioned freezing; the current experiment observed the long-term effects of neonatal inflammatory pain on conditioned fear using a weak conditioning protocol.
Learn More >A child maltreatment history is reported more frequently among adults with chronic pain compared to the general population; unfortunately, studies have primarily relied upon retrospective maltreatment reports by adults with chronic pain. This prospective study assessed pain symptoms in a cohort of young adult women with a documented history of child maltreatment, compared with a matched cohort of women who did not experience childhood maltreatment. Young women (N = 477) were recruited between ages 14-17 years and followed annually to age 19. Of these women, 57% experienced maltreatment (i.e., physical, sexual, or emotional abuse, neglect; n = 273) substantiated by child welfare record. Maltreated women were demographically-matched to non-maltreated women, also confirmed by child welfare record. In adolescence, post-traumatic stress was assessed. Women were contacted as young adults (Mage = 24.76; n = 383) and surveyed about their pain experiences, including the presence of pain in the past week, pain severity (0-10), and number of body areas with pain. Mediation path analyses examining the impact of maltreatment and adolescent post-traumatic stress on young adult pain were estimated via structural equation modeling. As adults, women who had experienced child maltreatment reported higher pain intensity, a greater number of pain locations, and were more likely to experience pain in the previous week than non-maltreated women. Adolescent post-traumatic stress partially explained the effects of maltreatment on pain. Young adult women who experienced child maltreatment are at higher risk for pain, particularly when they also experienced post-traumatic stress as adolescents.
Learn More >CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes.
Learn More >Fatigue is commonly reported by people with chronic pain. The purpose of the current study was to examine Acceptance and Commitment Therapy (ACT), based on the Psychological Flexibility (PF) model, for fatigue in chronic pain. This study included 354 adults attending an interdisciplinary ACT-oriented treatment for chronic pain. T-tests and analyses of clinically meaningful change were used to investigate participant improvements in fatigue interference after the treatment. Pearson's correlations and hierarchical regressions were conducted to investigate associations between improvement in fatigue interference and improvements in PF processes. Finally, mixed effects models were used to explore associations between baseline fatigue interference and changes in treatment outcome measures. Participants improved in fatigue interference (d=.37), pain, some PF processes, and daily functioning (d=.18-1.08). 39.7% of participants demonstrated clinically meaningfully improvements in fatigue interference. Changes in fatigue interference was associated with changes in pain, PF processes and daily functioning, |r|= .20-.46. Change in fatigue interference was associated with change in pain acceptance independent of change in pain, β=-.36, p<.001. However, baseline fatigue interference did not predict any treatment outcome. Overall, people with fatigue appeared to benefit from the ACT-oriented interdisciplinary treatment for chronic pain, and relatively higher levels of fatigue did not appear to impede this benefit. ACT-based treatments may benefit people with chronic pain and fatigue. Future studies including experimental designs, and studies investigating other PF processes, are needed to better understand the utility of ACT for co-morbid fatigue and pain.
Learn More >The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena. Yet, the majority of studies involve healthy participants. As the pain modulatory system may differ in healthy participants and patients with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each of these populations. PubMed, Embase, Scopus databases, and the Cochrane Library were searched for articles investigating the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokinergic (CCKergic) systems in placebo and nocebo effects in pain. Twenty-eight placebo and two nocebo studies were included. Vote counting was used to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid and vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were mixed. In patients with chronic pain, only four studies investigated neurotransmitters showing no involvement of the endogenous opioid system and mixed findings regarding the dopaminergic system. As to nocebo effects, two studies suggest that the CCKergic system is involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.
Learn More >Although burst and high-frequency (HF) spinal cord stimulation (SCS) relieve neuropathic pain, their effects on neuronal hyperexcitability have not been compared. Specifically, it is unknown how the recharge components of burst SCS-either actively balanced or allowed to passively return-and/or different frequencies of HF SCS compare in altering neuronal activity. Neuronal firing rates were measured in the spinal dorsal horn on day 7 after painful cervical nerve root compression in the rat. Motor thresholds (MTs) and evoked neuronal recordings were collected during noxious stimuli before (baseline) and after delivery of SCS using different SCS modes: 10 kHz HF, 1.2 kHz HF, burst with active recharge, or burst with passive recharge. Spontaneous firing rates were also evaluated at baseline and after SCS. The average MT for 10 kHz SCS was significantly higher (p < 0.033) than any other mode. Burst with passive recharge was the only SCS mode to significantly reduce evoked (p = 0.019) and spontaneous (p = 0.0076) firing rates after noxious pinch. This study demonstrates that HF and burst SCS have different MTs and effects on both evoked and spontaneous firing rates, indicating they have different mechanisms of providing pain relief. Since burst with passive recharge was the only waveform to reduce firing, that waveform may be important in the neurophysiological response to stimulation.
Learn More >To investigate the influence of clinical and demographic features on diagnostic delay in cluster headache patients, in order to discuss diagnostic pitfalls and raise disease awareness.
Learn More >Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published.
Learn More >Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level. The present study was designed to test the above hypothesis in a well-established electrophysiological model of migraine. Using anesthetized rats, we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation. Furthermore, pretreatment with L-368,899 (a selective oxytocin receptor antagonist, OTR) abolished the oxytocin-induced inhibition of trigeminovascular neuronal responses. This study provides the first direct evidence that oxytocin, probably by OTR activation at TCC level inhibited dural nociceptive-evoked action potential in this complex. Thus, targeting OTR at TCC could represent a new avenue to treat migraine.
Learn More >Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.
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