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.

Traditionally. opiates are considered to exert analgesic effects through actions within the central nervous system (CNS). Recently, however, the notion that opioid antinociception can be brought about by activation of opioid receptors located peripherally, i.e. outside the CNS, has gained more widespread recognition. One of the earliest reports was that of Wood in 1855 who showed that morphine elicited analgesic effects when applied topically to “painful areas” in the periphery. Numerous clinical and experimental reports of similar observations have occurred since. However. most of the former are merely anecdotal and many of the latter were discounted because of their lack of demonstration of the principal criterion for opioid receptor-mediated effects, namely naloxone (NAL) reversibility. Moreover, as already discussed in Wood’s paper, the question as to whether these effects result from a truly peripheral rather than from a central site of action (e.g. via uptake of the agent into the circulation and transport to the CNS) has been raised repeatedly. In this chapter, studies examining peripheral antinociceptive effects of opioids in animals and humans will be reviewed.

Opioid Analgesia at Peripheral Sites

Activation of opioid receptors on peripheral sensory nerve terminals by opioid peptides that are produced and released from immune cells can result in inhibition of inflammatory pain. This study tests the hypothesis that postoperative pain is attenuated endogenously through a local sympathetic neurotransmitter-activated release of opioids in patients undergoing knee surgery. We examined the expression of opioid peptides and adrenergic receptors in cells infiltrating inflamed synovial tissue and we hypothesized that intra-articular (i.a.) administration of the adrenergic receptor antagonist labetalol will increase postoperative analgesic consumption and/or pain intensity in these patients. In a double-blind, randomized manner, 75 patients undergoing therapeutic knee arthroscopy received i.a. placebo (20 ml saline) or labetalol (2.5 or 5 mg in 20 ml saline) at the end of surgery. Postoperative pain intensity was assessed by visual analog and verbal rating scales at rest and on exertion, and by the consumption of morphine via patient-controlled analgesia. Synovial biopsies were taken during the operation for double-immunofluorescence confocal microscopy studies. Alpha1- and beta2-adrenergic receptors were co-expressed in opioid peptide-containing cells. No significant difference was seen in pain scores, but patients receiving 2.5 mg labetalol requested significantly higher amounts of morphine. These findings are consistent with the notion that surgical stress induces sympathetically activated release of endogenous opioids from inflammatory cells and subsequent analgesia via activation of peripheral opioid receptors.

Blockade of intra-articular adrenergic receptors increases analgesic demands for pain relief after knee surgery

Traditionally, opioids exert analgesic effects through actions within the central nervous system (CNS) exclusively (1). Recently, however, evidence has begun to accumulate that opioid antinociception can be initiated by activation of opioid receptors located outside the CNS. One of the earliest repo

Peripheral mechanisms of opioid analgesia

This article reviews the role of analgesic drugs with a particular emphasis on opioids. Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g., perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current opioid crisis. We discuss epidemiological data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects.

Pain therapy - Are there new options on the horizon?

Currently, opioids targeting mu-opioid receptors are the most potent drugs for acute and cancer pain. However, opioids produce adverse side effects such as constipation, respiratory depression, or addiction potential. We recently developed (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a compound that does not evoke central or intestinal side effects due to its selective activation of mu-opioid receptors at low pH in peripheral injured tissues. Although we demonstrated that NFEPP effectively abolishes injury-induced pain, hyperalgesia, and allodynia in rodents, the efficacy of NFEPP in nonevoked ongoing pain remains to be established. Here, we examined reward, locomotor activity, and defecation in rats with complete Freund's adjuvant-induced paw inflammation to compare fentanyl's and NFEPP's potentials to induce side effects and to inhibit spontaneous pain. We demonstrate that low, but not higher, doses of NFEPP produce conditioned place preference but not constipation or motor disturbance, in contrast to fentanyl. Using a peripherally restricted antagonist, we provide evidence that NFEPP-induced place preference is mediated by peripheral opioid receptors. Our results indicate that a low dose of NFEPP produces reward by abolishing spontaneous inflammatory pain.

Christoph Stein

Papers

Opioid Analgesia at Peripheral Sites

Blockade of intra-articular adrenergic receptors increases analgesic demands for pain relief after knee surgery

Peripheral mechanisms of opioid analgesia

Pain therapy - Are there new options on the horizon?

Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain.