The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

/pdf/the-biopsychosocial-approach-to-chronic-pain-scientific-1047fjbjjh.pdf

The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions

Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes.

Mechanisms of Endocytosis

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Clathrin-mediated endocytosis is the endocytic portal into cells through which cargo is packaged into vesicles with the aid of a clathrin coat. It is fundamental to neurotransmission, signal transduction and the regulation of many plasma membrane activities and is thus essential to higher eukaryotic life. Morphological stages of vesicle formation are mirrored by progression through various protein modules (complexes). The process involves the formation of a putative FCH domain only (FCHO) initiation complex, which matures through adaptor protein 2 (AP2)-dependent cargo selection, and subsequent coat building, dynamin-mediated scission and finally auxilin- and heat shock cognate 70 (HSC70)-dependent uncoating. Some modules can be used in other pathways, and additions or substitutions confer cell specificity and adaptability.

/pdf/molecular-mechanism-and-physiological-functions-of-clathrin-2hpvjtbosd.pdf

Molecular mechanism and physiological functions of clathrin-mediated endocytosis

Membrane curvature is no longer seen as a passive consequence of cellular activity but an active means to create membrane domains and to organize centres for membrane trafficking. Curvature can be dynamically modulated by changes in lipid composition, the oligomerization of curvature scaffolding proteins and the reversible insertion of protein regions that act like wedges in membranes. There is an interplay between curvature-generating and curvature-sensing proteins during vesicle budding. This is seen during vesicle budding and in the formation of microenvironments. On a larger scale, membrane curvature is a prime player in growth, division and movement.

/pdf/membrane-curvature-and-mechanisms-of-dynamic-cell-membrane-2hm38oqsgo.pdf

Membrane curvature and mechanisms of dynamic cell membrane remodelling

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.

Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.

The activated form (p65) of nuclear factor kappa B (NF-kappa B) was found to be expressed in a sub-population (32%) of mixed diameter rat sensory neurons in L4 and L5 dorsal root ganglia, indicating that this transcription factor is involved in intracellular signalling in sensory neurons under physiological conditions. Four hours after crushing the sciatic nerve, ipsilateral p65 staining was abolished in a subgroup (60-70%) of these neurons. The contralateral side was unaffected by the injury and loss of NF-kappa B activity was not observed following sham surgery. Within 24 h of sciatic injury, ipsilateral p65 staining had recovered to control levels. We suggest that the decline in p65 after nerve injury was due to failure of retrograde axonal transport of trophic factor(s). Since neurotrophins and cytokines promote the survival of non-neuronal cells by activation of NF-kappa B, we believe that p65 may be critical for the resistance to apoptosis shown by adult sensory neurons.

Reduced nuclear factor κb (p65) expression in rat primary sensory neurons after peripheral nerve injury

Altered nociception, analgesia, and aggression in mice lacking the substance P receptor

Amphiphysin (Amph) is a src homology 3 domain-containing protein that has been implicated in synaptic vesicle endocytosis as a result of its interaction with dynamin. In a screen for novel members of the amphiphysin family, we identified Amph2, an isoform 49% identical to the previously characterized Amph1 protein. The subcellular distribution of this isoform parallels Amph1, both being enriched in nerve terminals. Like Amph1, a role in endocytosis at the nerve terminal is supported by the rapid dephosphorylation of Amph2 on depolarization. Importantly, the two isoforms can be coimmunoprecipitated from the brain as an equimolar complex, suggesting that the two isoforms act in concert. As determined by cross-linking of brain extracts, the Amph1-Amph2 complex is a 220- to 250-kDa heterodimer. COS cells transfected with either Amph1 or Amph2 show greatly reduced transferrin uptake, but coexpression of the two proteins rescues this defect, supporting a role for the heterodimer in clathrin-mediated endocytosis. Although the src homology 3 domains of both isoforms interact with dynamin, the heterodimer can associate with multiple dynamin molecules in vitro and activates dynamin's GTPase activity. We propose that it is an amphiphysin heterodimer that drives the recruitment of dynamin to clathrin-coated pits in endocytosing nerve terminals.

/pdf/amphiphysin-heterodimers-potential-role-in-clathrin-mediated-432n56wo3p.pdf

Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis.

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Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.

Reduced nuclear factor κb (p65) expression in rat primary sensory neurons after peripheral nerve injury

Altered nociception, analgesia, and aggression in mice lacking the substance P receptor

Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis.