抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

https://onlinelibrary.wiley.com/doi/epdf/10.1002/acr.20543

Measures of Adult Pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP)

Drug addiction, dysregulation of reward, and allostasis.

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

Descending control of pain.

A remedy to suppress the sensation of pain, especially in chronic inflammatory diseases, by means of expressing endogenous neuroendocrine peptides at the site of inflammation. In particular, the invention relates to the expression of POMC or CRF from locally injected DNA expression constructs, preferably covalently peptide-modified expression constructs.

Local pain-combating agent

Peripheral opioid receptors mediating analgesia in inflammation: activation by exogenous agonists and stress

We thank Cunha and Verri [1] for their constructive comments about our manuscript “Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain” [2]. They raise several important issues concerning the role of polymorphonuclear cells (PMN), of chemokines, and of IL-1 in the induction of inflammatory hyperalgesia. Initially, the authors mention that their group has previously shown that certain chemokines and cytokines can induce hyperalgesia [3, 4], whereas in our study, chemokine (CXCL1, CXCL2/3) injection did not cause hyperalgesia. We agree with their comment that this discrepancy is most likely a result of different behavioral methods used. This issue is discussed in detail in our manuscript [2]. Cunha and Verri then show data that local PMN infiltration [measured indirectly by myeloperoxidase (MPO) activity] and mechanical hyperalgesia (measured by the von Frey test) are low in early inflammation [i.e., 2 h post-complete Freund’s adjuvant (CFA)] and increase in parallel within the first 6 h of CFA injection into the rat paw. Based on these correlative data they postulate that i) early time-points of inflammation are not ideal, and ii) PMN depletion at later time-points would be required to analyze the role of PMN in inflammatory hyperalgesia. In response, we would first like to point out that in line with our previous study [5], we indeed detected a significant increase in the number of PMN at 2 h after CFA injection (1.9 10 PMN/paw) compared with noninflamed paws (0.3 10 PMN/paw; Fig. 4 in ref. [2]). In contrast, Cunha and Verri detected a nonsignificant increase in MPO activity at 2 h after CFA (calculated equivalent of 0.5 10 PMN/mg paw tissue) compared with noninflamed paws (0.25 10 PMN/mg tissue). However, there are important differences between the two methods of PMN quantification and data reporting. We quantified infiltrating PMN by enzymatic tissue digestion, preparation of single cell suspensions, and flow cytometry using a PMN-specific antibody, and Cunha and Verri measured MPO activity in whole paw tissue and indirectly calculated the number of PMN. PMN quantification of tissue extracts by spectrophotometric MPO measurement is affected by tissue myoglobin and hemoglobin, and gel filtration chromatography is recommended to obtain a linear relationship between MPO activity and PMN numbers [6]. Thus, in addition to MPO activity from infiltrating PMN, Cunha and Verri might have measured MPO activity from other sources, which may have resulted in an artifically high MPO activity in noninflamed tissue, and thus, they were unable to detect significant differences between noninflamed tissue and 2 h of inflammation. In our experiments, in line with previous immunohistochemical studies [7, 8], we found very few infiltrating immune cells in noninflamed tissue and a significant rise in PMN at 2 h of inflammation (Fig. 4 in ref. [2]). Furthermore, Cunha and Verri found a significant increase in infiltrating PMN and the intensity of hyperalgesia at 6 h after CFA injection and suggested that PMN depletion studies should be performed at this time-point. To address this issue, we performed additional experiments and determined PMN infiltration in the paw and mechanical nociceptive thresholds in the presence and absence of prior systemic PMN depletion. In these experiments, injection of CFA, PMN depletion, leukocyte quantification by flow cytometry, and measurement of nociceptive thresholds were performed as described in our manuscript [2] with one modification: Experiments were performed at 6 h post-CFA injection. We found that PMN (Fig. 1A) and monocytes/macrophages in the paw were reduced significantly by prior systemic PMN depletion (CFA: 1.2 0.4 vs. CFA PMN depletion: 0.3 0.1 10 cells/paw, P 0.05; t-test). In both cases, mechanical nociceptive thresholds were decreased significantly in comparison with noninflamed paws, and no significant differences were found as a consequence of prior PMN depletion (Fig. 1B, P 0.05, P 0.05, respectively; t-test). Thus, in line with our results at 2 h of inflammation [2], systemic PMN depletion effectively reduced the number of PMN at the site of inflammation but did not alter hyperalgesia at 6 h post-CFA. Thus, even at later time-points when PMN infiltration is higher, depletion does not affect inflammatory pain. Cunha and Verri [1] further comment on the role of IL-1 in inflammatory hyperalgesia. We agree that IL-1 might contribute to inflammatory hyperalgesia. However, we measured total IL-1 content in the paw and not IL-1 release. IL-1 content does not predict extracellular biologically active IL-1 concentrations, as it is stored in leukocytes, and it requires additional signals (e.g., ATP) for release [9]. It is speculative to assume that equal amounts of IL-1 are released under the different conditions (i.e., local injection of CXCR2 ligands or CFA). In addition to IL-1 , we determined PGE2 content in the paw. As PGE2 is not stored, content equals extracellular amounts. We found significantly higher PGE2 concentrations

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0506337

Comment on "Neutrophils: are they hyperalgesic or anti-hyperalgesic?"

U50,488H (U50) is a κ‐opioid receptor agonist exerting effective analgesia in animal pain models. Yet, side effects such as sedation and depression‐like symptoms mediated in the brain limit its therapeutic potential. In this study, tailor‐made core‐multishell (CMS) nanocarriers are presented containing U50 that, despite their small size, exhibit a pH‐dependent retention effect via non‐covalent interactions with the drug. The nanocarriers and their non‐functionalized counterparts are characterized regarding their release properties in vitro, including a theoretical modeling of the release parameters which show the beneficial features of the additional functionalization. Finally, the U50‐containing nanocarriers are tested in an in vivo rat model of inflammatory pain, with the results showing prolonged analgesic effect.

Tailor‐Made Core‐Multishell Nanocarriers for the Delivery of Cationic Analgesics to Inflamed Tissue

Experimental mono- and polyarthritis differentially intensify immunostaining of multiple proenkephalin- and prodynorphin-opioid peptides in lumbo-sacral spinal neurons of the rat ☆

Christoph Stein

Papers

Local pain-combating agent

Peripheral opioid receptors mediating analgesia in inflammation: activation by exogenous agonists and stress

Comment on "Neutrophils: are they hyperalgesic or anti-hyperalgesic?"

Tailor‐Made Core‐Multishell Nanocarriers for the Delivery of Cationic Analgesics to Inflamed Tissue

Experimental mono- and polyarthritis differentially intensify immunostaining of multiple proenkephalin- and prodynorphin-opioid peptides in lumbo-sacral spinal neurons of the rat ☆