Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings

Endocytic recycling is coordinated with endocytic uptake to control the composition of the plasma membrane. Although much of our understanding of endocytic recycling has come from studies on the transferrin receptor, a protein internalized through clathrin-dependent endocytosis, increased interest in clathrin-independent endocytosis has led to the discovery of new endocytic recycling systems. Recent insights into the regulatory mechanisms that control endocytic recycling have focused on recycling through tubular carriers and the return to the cell surface of cargo that enters cells through clathrin-independent mechanisms. Recent work emphasizes the importance of regulated recycling in such diverse processes as cytokinesis, cell adhesion and morphogenesis, cell fusion, and learning and memory.

Pathways and mechanisms of endocytic recycling.

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.

A comprehensive review of opioid-induced hyperalgesia.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/1878-0261.12155

Emerging functions of the EGFR in cancer

Racial and ethnic disparities in pain: causes and consequences of unequal care.

While a variety of cultural, psychological and physiological factors contribute to variability in both clinical and experimental contexts, the role of genetic factors in human pain sensitivity is increasingly recognized as an important element. This study was performed to evaluate genetic influences on variability in human pain sensitivity associated with gender, ethnicity and temperament. Pain sensitivity in response to experimental painful thermal and cold stimuli was measured with visual analogue scale ratings and temperament dimensions of personality were evaluated. Loci in the vanilloid receptor subtype 1 gene (TRPV1), delta opioid receptor subtype 1 gene (OPRD1) and catechol O-methyltransferase gene (COMT) were genotyped using 5' nuclease assays. A total of 500 normal participants (306 females and 194 males) were evaluated. The sample composition was 62.0% European American, 17.4% African American, 9.0% Asian American, and 8.6% Hispanic, and 3.0% individuals with mixed racial parentage. Female European Americans with the TRPV1 Val(585) Val allele and males with low harm avoidance showed longer cold withdrawal times based on the classification and regression tree (CART) analysis. CART identified gender, an OPRD1 polymorphism and temperament dimensions of personality as the primary determinants of heat pain sensitivity at 49 degrees C. Our observations demonstrate that gender, ethnicity and temperament contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 and OPRD1 single nucleotide polymorphisms.

Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament.

Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR). To address if cellular kinases regulate EGFR internalization, we used anisomycin, a potent activator of kinase cascades in mammalian cells, especially the stress-activated mitogen-activated protein (MAP) kinase subtypes. Here, we report that activation of p38 MAP kinase by anisomycin is sufficient to induce internalization of EGFR. Anisomycin and EGF employ different mechanisms to promote EGFR endocytosis as anisomycin-induced internalization does not require tyrosine kinase activity or ubiquitination of the receptor. In addition, anisomycin treatment did not result in delivery and degradation of EGFR at lysosomes. Incubation with a specific inhibitor of p38, or depletion of endogenous p38 by small interfering RNAs, abolished anisomycin-induced internalization of EGFR while having no effect on transferrin endocytosis, indicating that the effect of p38 activation on EGFR endocytosis is specific. Interestingly, inhibition of p38 activation also abolished endocytosis of EGFR induced by UV radiation. Our results reveal a novel role for p38 in the regulation of EGFR endocytosis and suggest that stimulation of EGFR internalization by p38 might represent a general mechanism to prevent generation of proliferative or anti-apoptotic signals under stress conditions.

Activation of p38 Mitogen-Activated Protein Kinase Promotes Epidermal Growth Factor Receptor Internalization

In mammals, the mucolipin family includes three members mucolipin-1, mucolipin-2, and mucolipin-3 (MCOLN1-3). While mutations in MCOLN1 and MCOLN3 have been associated with mucolipidosis type IV and the varitint-waddler mouse phenotype, respectively, little is known about the function and cellular distribution of MCOLN2. Here we show that MCOLN2 traffics via the Arf6-associated pathway and colocalizes with major histocompatibility protein class I (MHCI) and glycosylphosphatidylinositol-anchored proteins (GPI-APs), such as CD59 in both vesicles and long tubular structures. Expression of a constitutive active Arf6 mutant, or activation of endogenous Arf6 by transfection with EFA6 or treatment with aluminum fluoride, caused accumulation of MCOLN2 in enlarged vacuoles that also contain MHCI and CD59. In addition, overexpression of MCOLN2 promoted efficient activation of Arf6 in vivo, thus suggesting that MCOLN2 may have a role in the traffic of cargo through the Arf6-associated pathway. In support of this we found that overexpression of a MCOLN2 inactive mutant decreases recycling of CD59 to the plasma membrane. Therefore, our results indicate that MCOLN2 localizes to the Arf6-regulated pathway and regulates sorting of GPI-APs.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0854.2007.00619.x

Anitza San Miguel

Papers

Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament.

Activation of p38 Mitogen-Activated Protein Kinase Promotes Epidermal Growth Factor Receptor Internalization

Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs.