Spatial Distribution of the Cannabinoid Type 1 and Capsaicin Receptors May Contribute to the Complexity of Their Crosstalk

Angelika Varga has been supported by a European Union Marie Curie Intra-European Fellowship (254661), a Hungarian Social Renewal Operation Program (TÁMOP 4.1.2.E-13/1/KONV-2013-0010) and the Hungarian Brain Research program (KTIA_NAP_13-2-2014-0005) of the Hungarian Government. Agnes Jenes has been supported by a BJA/RCoA Project Grant. This work has also been supported, in part, by the BIOSS-2 Grant, Project A6.

CAPSAICIN- AND ANANDAMIDE-SENSITIVITY OF PRIMARY SENSORY NEURONS IS CONTROLLED BY VARIOUS COMPONENTS OF CROSSTALK BETWEEN THE CANNABINOID TYPE 1 AND THE CAPSAICIN RECEPTORS

The endogenous agent anandamide activates both the G protein-coupled cannabinoid type 1 (CB1) receptor and the capsaicin-responsive transient receptor potential vanilloid type 1 ion channel (TRPV1), which exhibit a high degree of co-expression and crosstalk in primary sensory neurons (PSN). We capitalized on the dual agonist feature of anandamide to characterize the CB1-TRPV1 crosstalk, which could be a considerable component of nociceptive processing in PSN. Although the excitatory effect of both anandamide and capsaicin is TRPV1-dependent, a significant number of capsaicin-responsive neurons do not respond to anandamide. The CB1 receptor antagonist rimonabant has little effect on anandamide-evoked responses or on the proportion of the anandamide- and capsaicin-responsive (ACR) neurons. However, rimonabant reduces the amplitude of capsaicin-evoked responses in ACR, but not in capsaicin-only-responsive (COR) cells. Deletion of the CB1 receptor reduces the proportion of ACR neurons without having any effect on the overall proportion of the capsaicin-responsive neurons (ACR + COR) or on the amplitude of capsaicin- or anandamide-evoked responses. All ACR and the great majority of COR neurons express the CB1 receptor mRNA. However, immunofluorescent staining as well as sodium dodecyl sulfate-digested freeze-fracture replica electronmicroscopy show that, the overwhelming majority of the two receptors are either in close association or segregated in the cytoplasmic membrane of various CB1 receptor – TRPV1 coexpressing neurons. These findings suggest that the CB1-TRPV1 crosstalk has various components which, depending on the downstream effectors and spatial relationship of the two receptors, regulate the activity of the capsaicin receptor in PSN