Allosteric modulation of G protein-coupled receptors as a novel therapeutic strategy in neuropathic pain

Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice.Unfortunately,current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions.As G protein-coupled receptors(GPCRs)are widely distributed throughout the body,including the pain transmission pathway and descending inhibition pathway,the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum.Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects.This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain,and discuss the potential benefits and adverse factors of this treatment.We will also concentrate on the development of biased agonists of GPCRs,and based on important examples of biased agonist development in recent years,we will describe universal strategies for designing structure-based biased agonists.It is foreseeable that,with the continuous improvement of GPCRs allosteric modulation and biased agonist theory,effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.

Long-term hydrological impacts of land use/land cover change from 1984 to 2010 in the Little River Watershed,Tennessee

Assessing long-term hydrological impacts of land use/land cover(LULC)change is of critical importance for land use planning and water resource management.The Little River Watershed,Tennessee,is an important watershed supporting drinking water and recreational activities within and around the Great Smoky Mountains National Park in the Unites States.However,the potential hydrological impacts of LULC change,especially urbanization in recent decades,are not quantified.This paper assessed the long-term impacts of LULC change on streamflow and non-point source pollution using the Soil and Water Assessment Tool(SWAT)and a detailed LULC record from 1984 to 2010.The SWAT was first calibrated and validated using observed streamflowin 2010 and then simulated using different LULC patterns in 1984-2010 to quantify the long-term hydrological impacts caused by the LULC change.Simulated results indicated a minor 3%increase in streamflow for the whole watershed from 1984 to 2010,but with a distinct spatial pattern.The increase in streamflow is closely related to urban development.Almost no streamflow increase occurred in the upper watershed within the national park,whereas>10%increase occurred in the lower watershed,especially in areas close to cities.Model simulation also suggested 34.6%reduction in sediment and about 10%reduction in nutrient loads from 1984 to 2010,closely related to the decrease in agricultural land.However,without calibration and validation,the simulated reduction in the sediment and nutrient loads may be problematic because SWAT mainly simulates the static LULC patterns,whereas LULC transitions,such as construction phases,may generate more sediment and nutrient loads.In addition,the simulation also did not account for the sediment and nutrients generated from stream bank erosion.