Journal: eNeuro
Article Title: Lack of Causal Roles of Cannabinoid and Dopamine Neurotransmitter Systems in Orbitofrontal and Piriform Cortex in Fentanyl Relapse in Rats
doi: 10.1523/ENEURO.0496-21.2022
Figure Lengend Snippet: Effect of fentanyl relapse on activity in OFC and Pir cells expressing Cnr1 , Drd1 , and Drd2 . A , Timeline of experiment 1. B , Self-administration. Number of reinforced responses (food: 5 pellets/reinforcer; fentanyl 2.5 μg/kg/infusion) during the 6-h sessions. C , Discrete choice (voluntary reduction in self-administration). Number of food-reinforced responses and fentanyl infusions earned during the 3-h choice sessions (20 trials/session). D , Relapse tests. Number of active and inactive lever presses during the 60-min test session (left) and the 15-min time course (right). E , From left to right, Number of Fos + cells per mm 2 , number of Cnr1 + cells per mm 2 , number of Fos + Cnr1 double-labeled cells in OFC and Pir, number of Cnr1 + Vgat double-labeled cells per mm 2 , and number of Fos + Cnr1 + Vgat triple-labeled cells per mm 2 in OFC. Representative images showing Fos (white), Cnr1 (green), or Vgat (red)-expressing cells (20× magnification, scale bar = 25 μm). White arrow denotes Fos -positive cell, green arrow denotes Cnr1 -positive cell, and red arrow denotes Vgat -positive cells. Double-labeled cells are denoted by both a white and green arrow. Triple-labeled cells are denoted by a white, green, and red arrow. F , From left to right, Number of Fos + cells per mm 2 , number of Drd1 + and Drd2+ cells per mm 2 , and number of Fos + Drd1 and Fos+Drd2 double-labeled cells in OFC and Pir. Representative images showing Fos (white), or Drd1 (red), Drd2 (green; 20× magnification, scale bar = 25 μm). White arrow denotes Fos -positive cell, red arrow denotes Drd1 -positive cell, and green arrow denotes Drd2 -positive cell. Double-labeled cells are denoted by both a white and green or red arrow ( n = 6–8 per group); * p ≤ 0.05, different from the No Test group ( E , F ). Data are mean ± SEM. Individual data are shown separately by sex (males = circles, females = triangles) in D–F . OFC, orbitofrontal cortex; Pir, piriform cortex.
Article Snippet: We received the CB1 receptor antagonist AM251 from Sigma (catalog #A6266) and the CB1 receptor agonist WIN55,212-2 from Tocris (catalog #1038) and dissolved them in sterile saline with 8% DMSO, and 5% Tween 80 for intracranial injections.
Techniques: Activity Assay, Expressing, Labeling
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![Tactile (A) and thermal (B) sensory testing data for diabetic mice receiving either intranasal or intraperitoneal nabilone at low, medium, or high dose, with comparison to non-diabetic mice and saline delivery is shown . Those diabetic mice receiving medium or high doses of intranasal or intraperitoneal nabilone had amelioration of both tactile allodynia and thermal hyperalgesia beginning at week 7 when nociceptive behaviors began. This protection against the development of the neuropathic pain state disappeared after discontinuation of nabilone at week 14. Tactile ( C ) and thermal ( D ) sensory testing data for mice with diabetes receiving either intranasal or intraperitoneal WIN55212-2 at low, medium, or high dose, with comparison to non-diabetic mice receiving intranasal or intraperitoneal saline is also demonstrated. Those diabetic mice receiving high doses of intranasal or intraperitoneal WIN55212-2 had amelioration of tactile allodynia beginning at week 7 when nociceptive behaviors began, while thermal hyperalgesia was modulated by either medium or high doses of intranasal or intraperitoneal WIN55212-2. This protection against the development of the neuropathic pain state disappeared after discontinuation of nabilone at week 14, after which all diabetic mouse cohorts had comparable levels of tactile allodynia and thermal hyperalgesia. For both tactile ( A, C ) and thermal ( B, D ) testing, significant differences were detected between the diabetic mouse group receiving medium (γ) or high doses (θ) of intranasal nabilone/WIN55212-2 or medium (φ) high (Ψ) doses of intraperiteonal nabilone/WIN55212-2 when compared to the diabetic mouse group receiving low dose intranasal or intraperitoneal nabilone/WIN55212-2 respectively (non-matched ANOVA tests, F -values range between 0.76-3.07 for indicated groups and time points, n ≥ 4 , p < 0.05). Area under the curve (AUC) measurements were also significantly different in each case (p < 0.05) for weeks 1-13, but not for assessment of tactile allodynia in mice receiving any dose/route for WIN55212-2 ( C ). [n = 4-10 mice in each mouse cohort for each time point]](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_5559/pmc02845559/pmc02845559__1744-8069-6-16-9.jpg)
![Tactile (A) and thermal (B) sensory testing data for mice with established diabetes receiving either intranasal or intraperitoneal cannabinoid agents, with comparison to non-diabetic mice and saline delivery . Diabetic mice receiving medium and high doses of intranasal nabilone or WIN55212-2 had improvement of thermal hyperalgesia +/- tactile allodynia beginning at week 13 when interventions began. Stoppage of cannabinoid agents saw resumption of the full neuropathic pain state at week 21. For both tactile ( A ) and thermal ( B ) testing, significant differences were detected between the diabetic mouse group receiving moderate (γ) or high doses (θ) of intranasal cannabidiol or medium (χ) or high (τ) doses of intraperiteonal cannabidiol when compared to the diabetic mouse group receiving low dose intranasal or intraperitoneal cannabidiol at outset respectively (non-matched ANOVA tests, F -values range between 0.95-2.85 for indicated groups and time points, n ≥ 4 , p < 0.05). Area under the curve (AUC) measurements were also significantly different between the same comparison groups in each case (p < 0.05). [n = 4-10 mice in each mouse cohort for each time point]](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_5559/pmc02845559/pmc02845559__1744-8069-6-16-10.jpg)