Gastrin-Releasing Peptide

Spinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.

BackgroundItch is one of the major somatosensory modalities. Some recent findings have proposed that gastrin releasing peptide (Grp) is expressed in a subset of dorsal root ganglion (DRG) neurons and functions as a selective neurotransmitter for transferring itch information to spinal cord interneurons. However, expression data from public databases and earlier literatures indicate that Grp mRNA is only detected in dorsal spinal cord (dSC) whereas its family member neuromedin B (Nmb) is highly expressed in DRG neurons. These contradictory results argue that a thorough characterization of the expression of Grp and Nmb is warranted.FindingsGrp mRNA is highly expressed in dSC but is barely detectable in DRGs of juvenile and adult mice. Anti-bombesin serum specifically recognizes Grp but not Nmb. Grp is present in a small number of small-diameter DRG neurons and in abundance in layers I and II of the spinal cord. The reduction of dSC Grp after dorsal root rhizotomy is significantly different from those of DRG derived markers but similar to that of a spinal cord neuronal marker. Double fluorescent in situ of Nmb and other molecular markers indicate that Nmb is highly and selectively expressed in nociceptive and itch-sensitive DRG neurons.ConclusionThe majority of dSC Grp is synthesized locally in dorsal spinal cord neurons. On the other hand, Nmb is highly expressed in pain- and itch-sensing DRG neurons. Our findings provide direct anatomic evidence that Grp could function locally in the dorsal spinal cord in addition to its roles in DRG neurons and that Nmb has potential roles in nociceptive and itch-sensitive neurons. These results will improve our understanding about roles of Grp and Nmb in mediating itch sensation.

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.

ObjectiveAttention-deficit hyperactivity disorder is a neurodevelopmental disorder associated with metabolic and neuropeptidergic processes. Gastrin-releasing peptide and neuromedin B, which are bombesin-like peptides, have been studied only to a limited extent in adult attention-deficit hyperactivity disorder, despite their role in energy homeostasis and central nervous system function. The aim of this study was to evaluate gastrin-releasing peptide and neuromedin B levels in untreated adult attention-deficit hyperactivity disorder patients and to examine their relationship with clinical symptom severity.MethodsThis cross-sectional study included 55 untreated adult attention-deficit hyperactivity disorder patients and 32 healthy controls. Attention-deficit hyperactivity disorder diagnoses were confirmed using SCID-5/CV and DIVA 2.0, and symptom severity was assessed using the Adult Attention-Deficit Hyperactivity Disorder Self-Report Scale. Gastrin-releasing peptide and neuromedin B levels in fasting serum were measured using the ELISA method. Group comparisons, Pearson correlations, hierarchical regression, and receiver operating characteristic analyses were performed.ResultsGastrin-releasing peptide (22.83±24.18 pg/mL) and neuromedin B (1.83±2.86 pg/mL) levels were significantly lower in the attention-deficit hyperactivity disorder group compared to the control group (p=0.004 and p=0.037, respectively). Gastrin-releasing peptide and neuromedin B levels were negatively correlated with Attention-Deficit Hyperactivity Disorder Self-Report Scale total and subscale scores (pConclusionThe findings suggest that gastrin-releasing peptide, in particular, may be associated with clinical symptom severity in adult attention-deficit hyperactivity disorder and is a potential biomarker candidate.