Inhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior

Rasheen Powell; Violet A Young; Kerri D Pryce; Garrett D Sheehan; Kwaku Bonsu; Abdulelah Ahmed; Arin Bhattacharjee

doi:10.1038/s41467-021-26100-6

Inhibiting endocytosis in CGRP⁺ nociceptors attenuates inflammatory pain-like behavior

Nat Commun. 2021 Oct 4;12(1):5812. doi: 10.1038/s41467-021-26100-6.

Authors

Rasheen Powell¹, Violet A Young², Kerri D Pryce¹, Garrett D Sheehan², Kwaku Bonsu¹, Abdulelah Ahmed¹, Arin Bhattacharjee^{3

4}

Affiliations

¹ Pharmacology and Toxicology, University at Buffalo - The State University of New York, Buffalo, NY, 14203, USA.
² Program for Neuroscience, University at Buffalo - The State University of New York, Buffalo, NY, 14203, USA.
³ Pharmacology and Toxicology, University at Buffalo - The State University of New York, Buffalo, NY, 14203, USA. [email protected].
⁴ Program for Neuroscience, University at Buffalo - The State University of New York, Buffalo, NY, 14203, USA. [email protected].

Abstract

The advantage of locally applied anesthetics is that they are not associated with the many adverse effects, including addiction liability, of systemically administered analgesics. This therapeutic approach has two inherent pitfalls: specificity and a short duration of action. Here, we identified nociceptor endocytosis as a promising target for local, specific, and long-lasting treatment of inflammatory pain. We observed preferential expression of AP2α2, an α-subunit isoform of the AP2 complex, within CGRP⁺/IB4^- nociceptors in rodents and in CGRP⁺ dorsal root ganglion neurons from a human donor. We utilized genetic and pharmacological approaches to inhibit nociceptor endocytosis demonstrating its role in the development and maintenance of acute and chronic inflammatory pain. One-time injection of an AP2 inhibitor peptide significantly reduced acute and chronic pain-like behaviors and provided prolonged analgesia. We evidenced sexually dimorphic recovery responses to this pharmacological approach highlighting the importance of sex differences in pain development and response to analgesics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Protein Complex 2 / antagonists & inhibitors
Adaptor Protein Complex 2 / genetics
Adaptor Protein Complex 2 / metabolism
Adaptor Protein Complex alpha Subunits / antagonists & inhibitors
Adaptor Protein Complex alpha Subunits / genetics
Adaptor Protein Complex alpha Subunits / metabolism
Animals
Calcitonin Gene-Related Peptide / metabolism*
Chronic Pain / drug therapy*
Chronic Pain / metabolism
Chronic Pain / physiopathology
Endocytosis / drug effects*
Epidermis / innervation
Female
Ganglia, Spinal / metabolism
Humans
Inflammation
Male
Mice
Neurons, Afferent / drug effects
Neurons, Afferent / metabolism
Nociceptors / drug effects*
Nociceptors / metabolism
Nociceptors / physiology
Peptides / administration & dosage
Peptides / metabolism
Peptides / pharmacology
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
RNA, Small Interfering / pharmacology

Substances

Adaptor Protein Complex 2
Adaptor Protein Complex alpha Subunits
Peptides
RNA, Small Interfering
adaptor protein complex 2, alpha 2 subunit
Calcitonin Gene-Related Peptide

Abstract

Publication types

MeSH terms

Substances

Grants and funding