YokoCo

The development of psychedelics as medicines faces several challenges.

Migraine is a widespread and debilitating neurological condition affecting more than a billion people worldwide. Thus, more effective migraine therapies are highly needed. In the last decade, two endogenous neuropeptides, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP), were identified to be implicated in migraine. Recently, introduction of monoclonal antibodies (mAbs) blocking the CGRP is the most important advance in migraine therapy for decades. However, 40% of patients are unresponsive to these new drugs. We believe that PACAP may be involved in these patients. Like CGRP, PACAP is located to sensory nerve fibers, it dilates cranial arteries, it causes migraine when infused into patients and it is a peptide that lends itself to antibody therapy. Also, recent studies suggest that the PACAP pathway is independent of the CGRP pathway. Understanding the signaling pathways of PACAP may therefore lead to identification of novel therapeutic targets of particular interest in patients unresponsive to anti-CGRP therapy. Accordingly, neutralizing mAb to PACAP is currently in clinical phase II development. The aim of the present review is, therefore, to give a thorough account of the existing data on PACAP, its receptors and its relation to migraine.

The physical limitations experienced by people with chronic pain (CP) produce a greater need for care and assistance, most of which is provided by an informal caregiver (IC). Despite the key role ICs play in the everyday lives of individuals living with CP, knowledge about their experiences and needs is limited. We aimed to address this limitation by exploring the experiences of IC of people with CP.

Despite accumulating evidence indicating reciprocal interrelations between pain and alcohol consumption, no prior work has examined pain as a proximal antecedent of drinking. The goal of the current study was to test the effects of experimental pain induction on ad-lib alcohol consumption among moderate-to-heavy drinkers without chronic pain ( = 237; 42% female; 37% Black; = 3.26). Participants were randomized to either pain-induction (capsaicin + thermal heat paradigm) or no-pain-control conditions. Experimental pain induction lasted for 15 minutes, during which ad-lib alcohol consumption was assessed using an established taste test paradigm. As hypothesized, results indicated that participants randomized to the pain-induction condition poured and consumed more alcohol and reached a higher peak blood alcohol concentration than those randomized to the no-pain condition (s < 0.05; η² range = 0.018-0.021). Exploratory analyses revealed the effects of pain on alcohol consumption to be most pronounced among participants who self-identified as male or Black (relative to female or White, respectively). These findings indicate that the experience of pain serves as a causal, situational motivator for alcohol consumption, and suggest that current drinkers may be susceptible to escalating their consumption of alcohol in the context of pain. Future research is needed to explicate observed differences in the effects of pain on drinking as a function of gender and race, and to extend this work to individuals with chronic pain and varying levels of alcohol use. Collectively, these findings may help inform the development of integrated treatments to address co-occurring pain and alcohol use. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is markedly impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a novel role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.

"Non-inflammatory" pain, pain that is not associated with measures of inflammation, is common in patients with inflammatory arthritis including rheumatoid arthritis (RA). One important cause of non-inflammatory pain is concomitant fibromyalgia. Systematic review has shown that fibromyalgia is common in inflammatory arthritis including RA affecting 1 in 5 patients and is associated with higher disease activity scores due to inflated tender joint count and patient global assessment. Consequently, many patients with RA and concomitant fibromyalgia may fail to reach treatment target and switch to alternate disease modifying drugs frequently. European Alliance of Association for Rheumatology has highlighted that concomitant fibromyalgia is an important consideration in assessing difficult-to-treat RA. The incidence and prevalence of fibromyalgia are higher in RA than the general population raising the possibility that fibromyalgia may be "secondary "to RA rather than a concomitant disease. The precise mechanisms whereby patients with RA develop fibromyalgia are unknown. In this review, we discussed fibromyalgia in RA, its clinical impact and epidemiology as well as data suggesting fibromyalgia might be "secondary". Lastly, we reviewed potential pathogenic mechanisms which included inflammatory cytokines sensitizing nociceptive neurones, temporal summation, also known as windup, from chronic pain and impaired coping from poor quality sleep and mental well-being. Deciphering the exact mechanisms may lead to treatment strategies that prevent development of secondary fibromyalgia and will address a common factor associated with difficult to treat RA.

While a causal relationship between pain-related fear and spinal movement avoidance in patients with chronic low back pain (CLBP) has frequently been postulated, evidence supporting this relationship is limited. This study aimed to test if decreases in pain-related fear or catastrophizing were associated with improvements in spinal biomechanics, accounting for possible changes in movement-evoked pain.