Biphalin, an enkephalin analog with unexpectedly high antinociceptive potency and low dependence liability in vivo, selectively antagonizes excitatory opioid receptor functions of sensory neurons in culture

In the developing vertebrate nervous system the survival of neurons becomes dependent on the supply of a neurotrophic factor from their targets when their axons reach these targets. To determine how the onset of neurotrophic factor dependency is coordinated with the arrival of axons in the target field, we have studied the growth and survival of four populations of cranial sensory neurons whose axons have markedly different distances to grow to reach their targets. Axonal growth rate both in vivo and in vitro is related to target distance; neurons with more distant targets grow faster. The onset trophic factor dependency in culture is also related to target distance; neurons with more distant targets survive longer before becoming trophic factor dependent. These data suggest that programmes of growth and survival in early neurons play an important role in coordinating the timing of trophic interactions in the developing nervous system.

Download Full-text

The role of intra-articular neuronal CCR2 receptors in knee joint pain associated with experimental osteoarthritis in mice

Arthritis Research & Therapy ◽

10.1186/s13075-021-02486-y ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Shingo Ishihara ◽

Alia M. Obeidat ◽

David L. Wokosin ◽

Dongjun Ren ◽

Richard J. Miller ◽

...

Keyword(s):

Knee Joint ◽

Sensory Neuron ◽

Sensory Neurons ◽

Direct Stimulation ◽

Sensory Afferents ◽

Neuronal Marker ◽

The Right ◽

Experimental Osteoarthritis ◽

In Vivo Calcium Imaging

Abstract Background C–C chemokine receptor 2 (CCR2) signaling plays a key role in pain associated with experimental murine osteoarthritis (OA) after destabilization of the medial meniscus (DMM). Here, we aimed to assess if CCR2 expressed by intra-articular sensory neurons contributes to knee hyperalgesia in the early stages of the model. Methods DMM surgery was performed in the right knee of 10-week-old male wild-type (WT), Ccr2 null, or Ccr2RFP C57BL/6 mice. Knee hyperalgesia was measured using a Pressure Application Measurement device. CCR2 receptor antagonist (CCR2RA) was injected systemically (i.p.) or intra-articularly (i.a.) at different times after DMM to test its ability to reverse knee hyperalgesia. In vivo Ca2+ imaging of the dorsal root ganglion (DRG) was performed to assess sensory neuron responses to CCL2 injected into the knee joint cavity. CCL2 protein in the knee was measured by ELISA. Ccr2RFP mice and immunohistochemical staining for the pan-neuronal marker, protein gene product 9.5 (PGP9.5), or the sensory neuron marker, calcitonin gene-related peptide (CGRP), were used to visualize the location of CCR2 on intra-articular afferents. Results WT, but not Ccr2 null, mice displayed knee hyperalgesia 2–16 weeks after DMM. CCR2RA administered i.p. alleviated established hyperalgesia in WT mice 4 and 8 weeks after surgery. Intra-articular injection of CCL2 excited sensory neurons in the L4-DRG, as determined by in vivo calcium imaging; responses to CCL2 increased in mice 20 weeks after DMM. CCL2, but not vehicle, injected i.a. rapidly caused transient knee hyperalgesia in naïve WT, but not Ccr2 null, mice. Intra-articular CCR2RA injection also alleviated established hyperalgesia in WT mice 4 and 7 weeks after surgery. CCL2 protein was elevated in the knees of both WT and Ccr2 null mice 4 weeks after surgery. Co-expression of CCR2 and PGP9.5 as well as CCR2 and CGRP was observed in the lateral synovium of naïve mice; co-expression was also observed in the medial compartment of knees 8 weeks after DMM. Conclusions The findings suggest that CCL2-CCR2 signaling locally in the joint contributes to knee hyperalgesia in experimental OA, and it is in part mediated through direct stimulation of CCR2 expressed by intra-articular sensory afferents.

Download Full-text

Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01240 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 10

Author(s):

Muzeyyen Ugur ◽

Lyes Derouiche ◽

Dominique Massotte

Keyword(s):

Opioid Receptor ◽

Functional Properties ◽

Mu Opioid Receptor ◽

Mu Opioid

Download Full-text

Widespread inhibition, antagonism, and synergy in mouse olfactory sensory neurons in vivo

10.1101/803908 ◽

2019 ◽

Cited By ~ 1

Author(s):

Shigenori Inagaki ◽

Ryo Iwata ◽

Masakazu Iwamoto ◽

Takeshi Imai

Keyword(s):

Sensory Neurons ◽

Calcium Imaging ◽

Odorant Receptor ◽

Sensory Information ◽

Olfactory Sensory Neurons ◽

Axon Terminals ◽

Two Photon ◽

Odor Mixtures ◽

The Brain

SUMMARYSensory information is selectively or non-selectively inhibited and enhanced in the brain, but it remains unclear whether this occurs commonly at the peripheral stage. Here, we performed two-photon calcium imaging of mouse olfactory sensory neurons (OSNs) in vivo and found that odors produce not only excitatory but also inhibitory responses at their axon terminals. The inhibitory responses remained in mutant mice, in which all possible sources of presynaptic lateral inhibition were eliminated. Direct imaging of the olfactory epithelium revealed widespread inhibitory responses at OSN somata. The inhibition was in part due to inverse agonism toward the odorant receptor. We also found that responses to odor mixtures are often suppressed or enhanced in OSNs: Antagonism was dominant at higher odor concentrations, whereas synergy was more prominent at lower odor concentrations. Thus, odor responses are extensively tuned by inhibition, antagonism, and synergy, at the early peripheral stage, contributing to robust odor representations.

Download Full-text