The Majority of Dorsal Spinal Cord Gastrin Releasing Peptide is Synthesized Locally Whereas Neuromedin B is Highly Expressed in Pain- and Itch-Sensing Somatosensory Neurons

Abstract

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.

The TGR5 receptor mediates bile acid–induced itch and analgesia

“…The GRP released from this preparation could derive from the central projections of DRG neurons or from spinal neurons. Although GRP has been detected in DRG neurons (10,42), GRP is more prominently expressed by spinal neurons, including those within laminae I and II of the dorsal horn (50). We detected GRP-IR in both locations.…”

“…GRP is an itch-selective transmitter (10,11), and leucine-enkephalin (Leu-ENK) induces both itch and analgesia (5,26). GRP has been detected in DRG and spinal cord (10,42,50), and Leu-ENK is present in the spinal cord (51). To assess whether TGR5 regulates release of these neuropeptides, segments of spinal cord with attached dorsal roots were superfused with BAs and a TGR5-selective agonist (10, 100, or 500 μM, 60 minutes superfusion), and neuropeptide release was measured by ELISA.…”

Potential New Therapeutic Targets for Pathological Pruritus

“…79) Neuromedin B is mainly expressed in small-sized sensory neurons. 72) Intracerebroventricular injections of neuromedin B (and of GRP) elicits scratching in rats, 80) but intrathecal injection of neuromedin B elicits pain-like behaviors. 81) Toll-like receptors mediate innate immune responses and recognize pathogen-associated molecule patterns.…”

“…GRP is expressed in a small subset of peptidergic primary afferent neurons and a subset of neurons in the superficial dorsal horn. 72,73) Intrathecal administration of a bombesin-saporin conjugate produces the selective ablation of BB 2 receptor-expressing spinal neurons, without effect on BB 1 receptor-expressing spinal neurons. 74) This treatment markedly reduces scratching responses to intradermal injections of many pruritogenic substances such as histamine, compound 48/80, serotonin, endothelin-1, PAR 2 agonist, and chloroquine.…”

TRP Channels and Pruritus

“…A most recent study suggests that neuromedin B, a GRP and bombesin analogue peptide, is highly and selectively expressed in on itch and pain sensitive neurons in dorsal root ganglia (DRG). Moreover, neuromedin B was suggested to play a role in neurotransmission between DRG sensory neurons and spinal cord interneurons whereas GRP is mostly expressed on spinal cord neurons [31]. These results indicate the urgent need to re-evaluate the concept about the role of GRP in itch transmission since it may also act at another level of itch processing pathway than earlier studies suggested.…”