Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain

Danilo De Gregorio, Ryan J McLaughlin, Luca Posa, Rafael Ochoa-Sanchez, Justine Enns, Martha Lopez-Canul, Matthew Aboud, Sabatino Maione, Stefano Comai, Gabriella Gobbi, Danilo De Gregorio, Ryan J McLaughlin, Luca Posa, Rafael Ochoa-Sanchez, Justine Enns, Martha Lopez-Canul, Matthew Aboud, Sabatino Maione, Stefano Comai, Gabriella Gobbi

Abstract

Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT)1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact on models of neuropathic pain are unknown. First, using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Acute and repeated CBD administration on firing activity of DRN 5-HT neurons in naive rats. (A) Representation of coronal sections of the rat brain with the photomicrograph of the recording site in the DRN. Central gray dorsal (CGD); central gray lateral ventral (CGLV); aqueduct (Aq). The white arrow indicates the site of the electrode recording labeled with pontamine sky blue dye. (B) The typical spike waveform of 5-HT neuron. (C) Acute intravenous (i.v.) CBD administration decreases firing rate of DRN 5-HT neurons (n = 9), prevented by previous i.v. injection of WAY 100635 (WAY, n = 4) and CPZ (n = 4) but not by AM 251 (n = 4). Each point of the line represents mean ± SEM expressed as percentage of baseline before injections of veh, CBD, or antagonists. White arrow indicates the injection of veh, WAY, CPZ, or AM 251, and black arrow indicates the beginning of cumulative CBD injection. (D) WAY, CPZ, and AM 251 do not affect the basal 5-HT firing rate activity. (E-H) Representative firing rate histograms showing the acute response of 5-HT neurons to CBD alone (E) and with previous injection of WAY (F), CPZ (G), and AM 251 (H). Black arrows indicate sequence of a single injection of antagonists and of increasing doses of CBD. The cumulative doses are indicated on top of each arrow. Two-way ANOVA for RM followed by Bonferroni post hoc comparisons. *P < 0.05 and ***P < 0.001 vs veh; P < 0.001 vs CBD. (I) Mean firing DRN 5-HT activity of naive rats treated with veh (65 recorded neurons in 4 rats) or with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) (77 neurons recorded in 4 rats). Each bar represents mean ± SEM and each point represents a single neuron recorded in each group. The Student unpaired 2-tailed t test. ***P < 0.001 vs veh. (J) Simple linear regression analysis showing relationship between degree of suppression of 5-HT firing activity in the DRN and the dose of LSD administered i.v. in naive rats treated for 7 days with vehicle or CBD (5.0 mg/kg/day, s.c.). ANOVA, analysis of variance; CBD, cannabidiol; CPZ, capsazepine; DRN, dorsal raphe nucleus; N.S., not significant; RM, repeated measures.
Figure 2.
Figure 2.
Repeated CBD treatment increases paw withdrawal threshold and prevents anxiety-like behavior in the OFT, EPMT, and NSFT after SNI surgery. (A) Scheme illustrating the timing of SNI induction, behavioral and electrophysiological experiments. (B) Mechanical hypersensitivity was measured with von Frey filaments at day 15 (D0), 19 (D5), and 23 (D7) after SNI surgery. Sham rats treated with veh (n = 6) or CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days, n = 6) and SNI rats treated with veh (n = 9) and CBD (5 mg/kg/day, s.c., for 7 days, n = 9) were tested. Each point of the line represents mean ± SEM expressed as mean of 50% paw withdrawal threshold (g). Three-way ANOVA followed by Bonferroni post hoc comparisons. ***P < 0.001 vs sham/veh; ###P < 0.001 vs SNI/veh at D7. (C) Horizontal movement traces in the OFT of sham and SNI rats treated with veh or CBD (5 mg/kg/day, s.c., for 7 days). (D-F) Distance travelled (cm) (D), time spent (s) in the central area (E), and number of entries in the central area (F) of the OFT. Sham rats treated with veh (n = 9) or CBD (5 mg/kg/day, s.c., for 7 days, n = 9) and SNI rats treated with veh (n = 9) and CBD (5 mg/kg/day, s.c., for 7 days, n = 9) were tested. Each bar represents mean ± SEM. In D-F, each point represents data from an individual rat. Two-way ANOVA followed by Bonferroni post hoc comparisons. *P < 0.05 and ***P < 0.001 vs sham/veh; ###P < 0.001 vs SNI/veh. (G) Time of immobility (s) in the FST. (H and I) Percentage of time (%) (H) spent in the open arms in the EPMT and head dipping duration (s) (I). Each bar represents mean ± SEM. (J) Horizontal movement traces in the EPMT of sham and SNI rats treated with veh or CBD (5 mg/kg/day, s.c., for 7 days). (K and L) Latency to feed (s) in the novel (K) and familiar (L) environments in the NSFT. Each symbol represents mean ± SEM. Sham rats treated with veh (n = 8) or CBD (5 mg/kg/day, s.c., for 7 days, n = 9) and SNI rats treated with veh (n = 9) and CBD (5 mg/kg/day, s.c., for 7 days, n = 9) were tested. In G-I, each point represents data from an individual rat. Two-way ANOVA followed by Bonferroni post hoc comparisons. **P < 0.01 vs sham/veh., #P < 0.05, and ##P < 0.01 vs SNI/veh. ANOVA, analysis of variance; CBD, cannabidiol; EPMT, elevated plus maze test; FST, forced swim test; N.S., not significant; NSFT, novelty-suppressed feeding test; OFT, open-field test; SNI, spared nerve injury.
Figure 3.
Figure 3.
TRPV1 antagonism blocked the antinociceptive, but not the anxiolytic effects, of repeated CBD administration in SNI rats. (A) Scheme illustrating the timing of SNI induction, behavioral and electrophysiological experiments. (B) Mechanical hypersensitivity was measured with von Frey filaments at day 15 (D0), 19 (D5), and 23 (D7) after SNI surgery. Spared nerve injury rats treated with veh (n = 9), CBD alone (5 mg/kg/day, subcutaneously [s.c.], for 7 days, n = 9), or in combination with CPZ (10 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and CPZ alone (10 mg/kg/day, s.c., for 7 days, n = 7) were tested. Each point of the line represents mean ± SEM expressed as mean of 50% paw withdrawal threshold (g). Two-way ANOVA for repeated measures followed by Bonferroni post hoc comparisons. ***P < 0.001 vs SNI/veh; ###P < 0.001 vs SNI/CPZ + CBD at D7. (C) Horizontal movement traces in the OFT of SNI rats treated with veh, CBD alone (5 mg/kg/day, s.c., for 7 days), or in combination with CPZ (10 mg/kg/day, s.c., for 7 days, 10 minutes before CBD) and CPZ alone (10 mg/kg/day, s.c., for 7 days). (D-F) Distance travelled (cm) (D), time spent (s) in the central area (E), and number of entries in the central area (F) of the OFT. Spared nerve injury rats treated with veh (n = 9), CBD alone (5 mg/kg/day, s.c., for 7 days, n = 9), or in combination with CPZ (10 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and CPZ alone (2 mg/kg, s.c., for 7 days, n = 7) were tested. Each bar represents mean ± SEM. In D-F, each point represents data from an individual rat. One-way ANOVA followed by Bonferroni post hoc comparisons. *P < 0.05 and **P < 0.01 vs SNI/veh. (G) Percentage of time (%) spent in the open arms in the EPMT. Each bar represents mean ± SEM. (H) Horizontal movement traces in the EPMT of SNI rats treated with veh (n = 9), CBD alone (5 mg/kg/day, s.c., for 7 days, n = 9), or in combination with CPZ (10 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and CPZ alone (10 mg/kg/day, s.c., n = 7) were tested. (I and J) Latency to feed (s) in the novel (I) and familiar (J) environments in the NSFT. Each symbol represents mean ± SEM. In G, each point represents data from an individual rat. One-way ANOVA followed by Bonferroni post hoc comparisons. *P < 0.05, **P < 0.01, and ***P < 0.001 vs SNI/veh. ANOVA, analysis of variance; CBD, cannabidiol; CPZ, capsazepine; EPMT, elevated plus maze test; N.S., not significant; NSFT, novelty-suppressed feeding test; OFT, open-field test; SNI, spared nerve injury.
Figure 4.
Figure 4.
5-HT1A antagonism partially prevented antinociception and completely blocked the anxiolytic properties of repeated CBD administration in SNI rats. (A) Scheme illustrating the timing of SNI induction, behavioral and electrophysiological experiments. (B) Mechanical hypersensitivity was measured with von Frey filaments at day 15 (D0), 19 (D5), and 23 (D7) after SNI surgery. Spared nerve injury rats treated with veh (n = 9), CBD alone (5 mg/kg/day, subcutaneously [s.c.], for 7 days, n = 9), or in combination with WAY (2 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and WAY alone (2 mg/kg/day, s.c., for 7 days, n = 7) were tested. Each point of the line represents mean ± SEM expressed as mean of 50% paw withdrawal threshold (g). Two-way ANOVA for repeated measures followed by Bonferroni post hoc comparisons. ***P < 0.001 vs SNI/veh; ##P < 0.01 vs SNI/WAY + CBD at D7. (C) Horizontal movement traces in the OFT of SNI rats treated with veh, CBD alone (5 mg/kg/day, s.c., for 7 days), or in combination with CPZ (10 mg/kg/day, s.c., for 7 days, 10 minutes before CBD) and WAY alone (2 mg/kg/day, s.c., for 7 days). (D-F) Distance travelled (cm) (D), time spent (s) in the central area (E), and number of entries in the central area (F) of the OFT. Spared nerve injury rats treated with veh (n = 9), CBD alone (5 mg/kg/day, s.c., for 7 days, n = 9), or in combination with WAY (2 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and WAY alone (2 mg/kg, s.c., for 7 days, n = 7) were tested. Each bar represents mean ± SEM. In D-F, each point represents data from an individual rat. One-way ANOVA followed by Bonferroni post hoc comparisons. **P < 0.01 vs SNI/veh; #P < 0.05; and ##P < 0.01 vs SNI/CBD. (G) Percentage of time (%) spent in the open arms in the EPMT. Each bar represents mean ± SEM. (H) Horizontal movement traces in the EPMT of SNI rats treated with veh (n = 9), CBD alone (5 mg/kg/day, s.c., for 7 days, n = 9), or in combination with WAY (2 mg/kg/day, s.c., for 7 days, 10 minutes before CBD, n = 8) and WAY alone (2 mg/kg/day, s.c., n = 7) were tested. (I and J) Latency to feed (s) in the novel (I) and familiar (J) environments in the NSFT. Each symbol represents mean ± SEM. In G, each point represents data from an individual rat. One-way ANOVA followed by Bonferroni post hoc comparisons. **P < 0.01 vs SNI/veh; #P < 0.05 vs SNI/CBD. ANOVA, analysis of variance; CBD, cannabidiol; CPZ, capsazepine; EPMT, elevated plus maze test; N.S., not significant; NSFT, novelty-suppressed feeding test; OFT, open-field test; SNI, spared nerve injury.
Figure 5.
Figure 5.
Repeated CBD treatment prevents SNI-induced alterations in DRN 5-HT neuronal activity. (A) Mean DRN 5-HT firing activity (spikes/s). (B) Representative firing rate histograms of the mean DRN 5-HT firing rate activity recorded in sham and SNI rats treated with veh or CBD (5.0 mg/kg/day, for 7 days, subcutaneously [s.c.]). (C) Mean DRN 5-HT COV (%). Each bar represents mean ± SEM. Two-way ANOVA followed by Bonferroni post hoc comparisons. (D) Representative rate histograms recorded from a DRN neuron excited (top) or not (bottom) by mechanical pinch to the operated hind paw. (E) Contingency interleaved bars showing percentage (%) of DRN 5-HT neurons excited or not by mechanical paw pinch stimulation. (F) Contingency stacked bars showing percentage (%) of bursting and nonbursting DRN 5-HT neurons (the χ2 test). (G) Mean number of DRN 5-HT neuron recorded per electrode descent. Sham rats treated with veh (n = 5) or CBD (5 mg/kg/day, s.c., for 7 days) (n = 5) and SNI rats treated with veh (n = 4) and CBD (5 mg/kg/day, s.c., for 7 days) (n = 7) were tested. Two-way ANOVA followed by Bonferroni post hoc comparisons. In A and C, each point represents a single neuron recorded in each group. In F, each point represents data from an individual rat. **P < 0.01, ***P < 0.001 vs sham/veh., #P < 0.05, and ###P < 0.001 vs SNI/veh. ANOVA, analysis of variance; CBD, cannabidiol; COV, coefficient of variation; DRN, dorsal raphe nucleus; SNI, spared nerve injury.

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