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The perception of odors is influenced by a variety of neuromodulators, and there is growing evidence that modulation already takes place in the olfactory epithelium. Here we report on cannabinergic actions in the olfactory epithelium of Xenopus laevis tadpoles. First we show that CB1 receptor-specific antagonists AM251, AM281, and LY320135 modulate odor-evoked calcium changes in olfactory receptor neurons. Second, we localize CB1-like immunoreactivity on dendrites of olfactory receptor neurons. Finally, we describe the cannabinergic influence on odor-induced spike-associated currents in individual olfactory receptor neurons. Here we demonstrate that the cannabinergic system has a profound impact on peripheral odor processing and discuss its possible function.
Fig. 1.
AM251 alters odor-evoked [Ca2+]i changes. (A) Overview of a X. laevis tadpolehead. The black rectangle indicates part of the animal's left OE. (Scale bar: 500 μm.) (B) Fluo4-AM stained acute slice preparation of the OE (image acquired at rest). PC, principal cavity. The yellow ovals indicate the ORN somata of this slice that responded to the AAMIX (100 μM). (Scale bar: 10 μm.) (C) [Ca2+]i transients of individual ORNs upon repeated applications of the AAMIX. The intraepithelial location of the four cells shown is indicated in B. [Scale bars: 10 s and δF/F 100% (cells 1 and 2) and 10 s and δF/F 50% (cell 3 and cell 4).] (D) After addition of AM251 (5 μM) to the bath solution the AAMIX-evoked ORN responses (black traces) were modulated (red traces). After 12 min of drug washout the odor-induced [Ca2+]i transients recovered completely (green traces). [Scale bars: 10 s and δF/F 100% (cells 1 and 2) and 10 s and δF/F 50% (cells 3 and 4).] (E) AM251 does not interfere with odorant binding at olfactory receptors. Application of AM251 (50 μM) alone (E1) did not elicit any response. (E2 and E3) Odorant-induced [Ca2+]i transient upon application of the AAMIX (50 μM) alone (E2) and [Ca2+]i transient induced by a coapplication of the antagonist (AM251, 50 μM) and 50 μM AAMIX (E3). The reproducibility of the [Ca2+]i transients was not altered by the presence of the antagonist (compare black and red traces). (Scale bars: 10 s and δF/F 100%.)
Fig. 2.
CB1 receptor-mediated antagonist action upon amino acid-sensitive ORNs. (A) The modulatory effects of AM281 (10 μM; red trace) on an AAMIX-evoked ORN response (black trace) could not be washed out within 2 or 5 min with bath solution alone (green trace and blue trace, respectively). (B) [Ca2+]i transient of an individual ORN upon application of the AAMIX (black trace). After addition of AM281 (10 μM) to the bath solution the AAMIX-evoked ORN response was suppressed (red trace). After 2 min of drug washout with HU210 (20 μM) in the bath solution, the odor-induced [Ca2+]i transient recovered almost completely (green trace). [Scale bars: 10 s and δF/F 50% (A) and 10 s and δF/F 100% (B).]
Fig. 3.
CB1 distribution in the OE of X. laevis tadpoles. (A) Slice of an OE with biocytin-avidin-stained ORNs (merged z-stack; 16 optical slices, total thickness 14.4 μm). (Scale bar: 20 μm.) (B) Immunoreactivity to an rCB1-NH antibody of the same slice (see Materials and Methods). (C) Merged z-stack of an OE treated with the anti-CB1 antibody after preadsorption with the immunizing protein (see Materials and Methods). (D–F) Higher magnification of the region indicated by the white rectangle in A (merged z-stack; four optical slices, total thickness 3.6 μm). (Scale bar: 10 μm.) (E) CB1-LI IR localized to dendritic processes. The somata of the ORNs are clearly IR-free. (F) Overlay of D and E. CB1-LI IR is clearly occurring at ORN dendrites.
Fig. 4.
CB1 antagonist AM251 alters odor-evoked electrical activity in individual ORNs. (A1) AAMIX-induced action potential-associated currents of an individual ORN. [Scale bars: 2 s and 20 pA (A1–A5).] The corresponding poststimulus time histogram is shown in B1. The superimposed red histogram comes from a successive AAMIX application (interstimulus interval 3 min; current trace not shown) and shows the high reproducibility of the odorant response. (A2–A4 and B2–B4) The modulatory effect of AM251 on the action potential-associated currents depends on the wash-in time of the antagonist. (A5 and B5) Recovery after 20-min drug washout. The time window of the original response is indicated by the gray-shaded area. (A6 and B6) Odor concentration time course. Shown is simulation of the odor dynamics during a single odorant application (see Materials and Methods). (C1–C5) Zoom of individual spike-associated currents, one from each current trace A1–A5 (trace duration 25 ms). (Scale bar: 40 pA.)
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