Accepted

The light-activated Transient Receptor Potential (TRP) channel is the founding member of a large and diverse family of channel proteins. The TRP (dTRP) channel, which generates the electrical response to light has been investigated in a great detail two decades before the first mammalian TRP channel was discovered. Thus, dTRP is unique among members of the TRP channel superfamily because its physiological role and the enzymatic cascade underlying its activation are established. In this article we outline the research leading to elucidation of dTRP as the light activated channel and focus on a major physiological property of the dTRP channel, which is indirect activation via a cascade of enzymatic reactions. These detailed pioneering studies, based on the genetic dissection approach, revealed that light activation of the TRP channel is mediated by G-Protein-Coupled Receptor (GPCR)-dependent enzymatic cascade, in which phospholipase C β (PLC) is a crucial component. This physiological mechanism of TRP channel activation was later found in mammalian TRPC channels. However, the initial studies on the mammalian TRPV1 channel indicated that it is activated directly by capsaicin, low pH and hot temperature (>42 °C). This mechanism of activation was apparently at odds with the activation mechanism of the TRPC channels in general and the light activated TRP/TRPL channels in particular, which are target of a GPCR-activated PLC cascade. Subsequent studies have indicated that under physiological conditions TRPV1 is also target of a GPCR-activated PLC cascade in the generation of inflammatory pain. The light-activated TRP channel is still a useful experimental paradigm because its physiological function as the light-activated channel is known, powerful genetic techniques can be applied to its further analysis, and signaling molecules involved in the activation of these channels are available.

In everyday clinical practice, healthcare professionals often meet chronic pain patients with a poor nutritional status. A poor nutritional status such as malnutrition, unhealthy dietary behaviors, and a suboptimal dietary intake can play a significant role in the occurrence, development, and prognosis of chronic pain. The relationship between nutrition and chronic pain is complex and may involve many underlying mechanisms such as oxidative stress, inflammation, and glucose metabolism. As such, pain management requires a comprehensive and interdisciplinary approach that includes nutrition. Nutrition is the top modifiable lifestyle factor for chronic non-communicable diseases including chronic pain. Optimizing one's dietary intake and behavior needs to be considered in pain management. Thus, this narrative review reports and summarizes the existing evidence regarding (1) the nutrition-related health of people experiencing pain (2) the underlying potential mechanisms that explain the interaction between nutrition and chronic pain, and (3) the role of nutrition screening, assessment and evaluation for people experiencing pain and the scope of nutrition practice in pain management. Future directions in the nutrition and chronic pain field are also discussed.

Compounds that activate only the G-protein signalling pathway represent an effective strategy for making safer opioids. In the present study, we report the design, synthesis and evaluation of two classes of novel PZM21 derivatives containing the benzothiophene ring and biphenyl ring group respectively as biased MOR agonists. New compounds SWG-LX-33 showed potent µOR agonist activity and produced µOR-dependent analgesia. SWG-LX-33 does not activate the β-arrestin-2 signalling pathway in   vitro  even at high concentrations. Computational docking demonstrated the amino acid residue ASN150 is critical for the weak efficacy and potency of MOR agonist in arrestin recruitment.

Itch is a common sensation which is amenable to disabling patients'life under pathological and chronic conditions. Shared assertion easily limits itch to chemical itch, without considering mechanical itch and alloknesis, its pathological counterpart. However, in recent years, our understanding of the mechanical itch pathway, particularly in the central nervous system, has been enhanced. In addition, Merkel complexes, conventionally considered as tactile end organs only responsible for light touch perception due to Piezo2 expressed by both Merkel cells and SA1 Aβ-fibres – low threshold mechanical receptors (LTMRs) – , have recently been identified as modulators of mechanical itch. However, the tactile end organs responsible for initiating mechanical itch remain unexplored. The consensus is that some LTMRs, either SA1 Aβ- or A∂- and C-, are cutaneous initiators of mechanical itch, even though they are not self-sufficient to finely detect and encode light mechanical stimuli into sensory perceptions, which depend on the entire hosting tactile end organ. Consequently, to enlighten our understanding of mechanical itch initiation, this article discusses the opportunity to consider Merkel complexes as potential tactile end organs responsible for initiating mechanical itch, under both healthy and pathological conditions. Their unsuspected modulatory abilities indeed show that they are tuned to detect and encode light mechanical stimuli leading to mechanical itch, especially as they host not only SA1 Aβ-LTMRs but also A∂- and C-fibres.