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Unpleasant somatosensory stimuli such as pain and itch can interrupt normal behavior. But survival can depend on resuming normal behavior before these challenges are fully resolved. The neural mechanisms that prioritize behavior when individuals are challenged with unpleasant somatosensory sensations, however, are not fully understood. Recently, we identified a neural circuit activated by hunger that can inhibit pain, prioritizing food seeking over tending to an injury. Here, we examine the ability of hunger, and neurons activated by hunger, to inhibit behavioral responses to another unpleasant somatosensory sensation – itch. We demonstrate that food deprivation inhibits scratching induced by 3 different pruritogenic stimuli: histamine, serotonin, and chloroquine. The inhibition of scratching correlates with the level of food deprivation, suggesting a cross-competition of alarm systems in the brain whereby more energy need more efficiently inhibits competing drives. Finally, we show that activity in hunger-sensitive, hypothalamic agouti-related protein (AgRP)-expressing neurons is sufficient to inhibit itch. Taken together, we showed that hunger or AgRP neuron activity inhibits itch, demonstrating that organisms have neural systems to filter and process ascending spinal signals activated by unpleasant somatosensory stimuli to prioritize salient needs.
Learn More >Pain is associated with emotional and physical suffering that severely impacts quality of life. Many guidelines for the treatment of moderate to severe cancer pain indicate the use of opioids. For a small proportion of the global population, opioids are readily accessible, but are consequently also subject to risk of overuse and misuse. On the other hand, many regions provide limited access to licensed opioid therapeutics and patients struggle for better pain management. The use of prescription opioids for treatment of severe cancer and acute pain is well established, but opioid use in chronic non-cancer pain is controversial and not supported by the literature. The opioid crisis and the increasing overdose fatalities in some countries have resulted in a resurgence of opiophobia in these countries, but even worse, amplified opiophobia in countries with lower opioid consumption. In this narrative review, we highlight how the opioid crisis of overuse in some countries can negatively impact appropriate access to opioids elsewhere. The availability of opioids for clinical and recreational use differs between countries worldwide-this is an important factor in determining the occurrence of a 'crisis of recreational use of opioids' or a 'crisis of under-prescription of opioids' for pain management.
Learn More >In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP84-104) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP84-104 via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-Seq and systems biology analyses revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP84-104 induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP84-104. According to sustained sensitization in tiers 1-2, T cell-related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP84-104-induced pain is T cell-dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multi-site, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP84-104 acts through sustained co-activation of metabolic, estrogen receptor-mediated nociceptive and autoimmune signaling programs.
Learn More >Independent of pain intensity, pain-specific distress is highly predictive of pain treatment needs, including the need for prescription opioids. Given the inherently distressing nature of chronic pain, there is a need to equip individuals with pain education and self-regulatory skills that are shown to improve adaptation and improve their response to medical treatments. Brief, targeted behavioral medicine interventions may efficiently address the key individual factors, improve self-regulation in the context of pain, and reduce the need for opioid therapy. This highlights the critical need for targeted, cost-effective interventions that efficiently address the key psychological factors that can amplify the need for opioids and increased risk for misuse. In this trial, the primary goal is to test the comparative efficacy of a single-session skills-based pain management class to a health education active control group among patients with chronic pain who are taking opioids.
Learn More >Recently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase.
Learn More >Adenosine triphosphate (ATP) and glutamate are associated with some headache conditions, and purinergic (P2X) and glutamatergic N-methyl-D-aspartate (NMDA) receptor-related processes in the medulla can modulate the effects of trigeminal nociceptive afferent inputs into the brainstem on craniofacial sensorimotor circuits. This study aimed to test whether neck muscle activity can be induced in rats by noxious stimulation of the frontal dura or superior sagittal sinus that involves P2X or NMDA receptor-dependent mechanisms.
Learn More >Burning mouth syndrome (BMS) is a chronic pain disorder affecting the oral cavity. Previous work has shown promising analgesic results of bodily illusions in other chronic pain conditions. The aim of this proof-of-concept, pilot study was to investigate whether bodily illusions reduce pain in BMS patients.
Learn More >PTSD symptoms and other negative psychosocial factors have been implicated in the transition from acute to persistent pain. Women (N = 375) who presented to an inner-city Emergency Department (ED) with complaints of acute pain were followed for 3 months. They completed a comprehensive battery of questionnaires at an initial visit, and provided ratings of pain intensity at the site of pain presented in the ED during 3 monthly phone calls. Latent class growth analyses were used to detect possible trajectories of change in pain intensity from initial visit to 3 months later. A 3-trajectory solution was found which identified three groups of participants. One group (early recovery; n = 93) had recovered to virtually no pain by the initial visit, whereas a second group (delayed recovery; n = 120) recovered to no pain only after one month. A third group (no recovery; n = 162) still reported elevated pain at 3-months post ED visit. The no recovery group reported significantly greater PTSD symptoms, anger and sleep disturbance, as well as lower social support, at initial visit than both the early recovery and delayed recovery groups. Results suggest that women with high levels of PTSD symptoms, anger, sleep disturbance and low social support who experience an acute pain episode serious enough to prompt an ED visit may maintain elevated pain at this pain site for at least three months. Such an array of factors may place women at increased risk of developing persistent pain following acute pain.
Learn More >Eight P2YR antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2YR antagonists rapidly (≤30 min) reversed mechano-allodynia, with maximal effects typically within 1 h after injection. Two analogues (4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid and -acetyl analogue , 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for (41%). A reversed triazole analogue reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2YR affinity. The mP2YR affinity was only partially predictive of efficacy, suggesting the influence of pharmacokinetic factors. Thus P2YR is a potential therapeutic target for treating chronic pain.
Learn More >Na1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of , has been reported to selectively activate Na1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for Na1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of Na1.3 activation in the hyperpolarizing direction by -11.3 mV, with no activity at Na1.1, Na1.2, and Na1.4-Na1.8. Additional activity was found at Na1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by -6.3 mV. In an attempt to convert Tf2 into an Na1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at Na1.3, although it still caused a small -5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the Na1.1/1.3 inhibitor ICA-121431 nor in Na1.9 mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at Na1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited.
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