DongYee Kim

An orally bioavailable MrgprX1-positive allosteric
modulator alleviates certain neuropathic pain–related
behaviors in humanized mice

The human Mas- related G protein–coupled receptor X1 (MrgprX1) represents a promising nonopioid analgesic tar
get because of its selective expression in primary nociceptive sensory neurons. Positive allosteric modulators (PAMs)
promote receptor signaling, depending on the availability of endogenous ligands, offering physiological selectivity
over orthosteric agonists. We developed an orally bioavailable MrgprX1 PAM, 6- tert- butyl- 5- (4- chlorophenyl)- 4- (2-
f
luoro- 6- (trifluoromethoxy)phenoxy)thieno[2,3- d]pyrimidine (BCFTP). BCFTP selectively potentiated the functional
response of MrgprX1 in HEK293 cells, was metabolically stable, and demonstrated a favorable in vitro safety profile.
BCFTP was orally bioavailable and distributed into the spinal cords of wild- type mice. BAM22, an endogenous ligand
for MrgprX1, was up- regulated in the spinal cord after nerve injury in both wild- type and humanized MrgprX1 mice
and was expressed in peptidergic and nonpeptidergic dorsal root ganglion neurons. Oral administration of BCFTP
dose- dependently inhibited heat hyperalgesia and spontaneous pain- like behavior but not mechanical hypersensi
tivity after sciatic chronic constrictive injury (CCI) in MrgprX1 mice. BCFTP did not have analgesic effects in Mrgpr
cluster knockout (Mrgpr−/−) mice, indicating that the analgesic effects in MrgprX1 mice were MrgprX1 dependent.
BCFTP enhanced BAM8- 22–induced, MrgprX1- mediated reduction of C- fiber eEPSC amplitudes in spinal lamina II
neurons, indicating inhibition of spinal nociceptive synaptic transmission. BCFTP did not induce tolerance or side
effects, such as itch, sedation, and motor incoordination, and had no rewarding properties. The mRNAs encoding
MrgprX1 and μ- opioid receptors were colocalized in human DRG neurons, and BCFTP synergistically enhanced mor
phine analgesia in CCI MrgprX1 mice. Our research suggests an approach for developing safer, orally bioavailable
MrgprX1 PAM as a nonopioid therapy for neuropathic pain.

Dongyee Kim

Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord

Abstract

Itch is a common side effect of opioid analgesics. The specific neurons mediating opioid-induced itch are still debated, and the mechanistic neuronal circuits remain elusive. Here, we show that the μ-opioid receptors (MOR) onneuropeptide Y (NPY)+inhibitory interneurons mediate opioid-induced itch at the spinal cord level in mice. The MOR gene Oprm1 is expressed in NPY+ neurons in the spinal dorsal horn, and specific deletion of Oprm1 in NPY+ interneurons abolishes intrathecal morphine-induced itch. Furthermore, gastrin releasing peptide (GRP)+ neurons are the direct downstream targets of NPY+ neurons. Mechanistically, morphine inhibits the neuronal excitability of NPY+ interneurons and reduces inhibitory synaptic inputs on GRP+ neurons, causing disinhibition of GRP+ neurons and further activation of gastrin releasing peptide receptor (GRPR)+ neurons. The NPY/neuropeptide Y receptor 1(NPY1R) system is essential for regulating GRP+neurons in opioid-induced itch. These findings reveal that intrathecal opioids act on MOR on NPY+ inhibitory neurons in the spinal dorsal horn, which subsequently disinhibit GRP-GRPR microcircuits, triggering the itch response.

Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain

DongYee Kim

TRESK background potassium channel regulates
MrgprA31 pruriceptor excitability, acute and
chronic itch

Dongyee Kim

http://dx.doi.org/10.1097/j.pain.0000000000003540