300. Delta-9-tetrahydrocannabinol (THC) alleviates neuropathic pain and insomnia through activation of the reticular thalamus
TL;DR
Acute systemic THC dose-dependently reduced SNL-induced mechanical allodynia and normalized sleep–wake architecture in NP rats, suggesting THC has potential therapeutic value for neuropathic pain with comorbid insomnia.
Abstract
Abstract Background Neuropathic pain (NP) constitutes a significant public health burden, impairing functional capacity and diminishing quality of life, largely due to its frequent association with comorbid conditions such as insomnia, depression, and anxiety. Therapeutic options for concurrently managing NP and comorbid insomnia remain limited. Delta-9-tetrahydrocannabinol (THC) has shown analgesic and hypnotic effects in preclinical and clinical studies, but the mechanisms underlying these actions—and the consistency of efficacy across NP models—remain incompletely understood. Aims & Objectives To characterize the effects of THC on insomnia associated with chronic NP induced by L5–L6 spinal nerve ligation (SNL) in rats, and to determine whether THC modulates pain-responsive neuronal activity in the reticular thalamic nucleus (RT) using in vivo extracellular recordings. Method Chronic NP was induced in Wistar rats using the L5/L6 SNL procedure. Fourteen days post-SNL, animals were assigned to three experimental arms: Mechanical allodynia: von Frey testing after acute THC (1, 1.5, 2, 2.5, or 5 mg/kg, i.p.) or vehicle (5% Tween 20, 5% PEG, saline, i.p.), assessed every 30 min for 5.5 h. Sleep–wake architecture: a subset received ECoG (three electrodes) and nuchal EMG (three electrodes) implants for continuous 6-h recordings (07:00–13:00) following THC (5 mg/kg, i.p.). Single-unit recordings: in vivo extracellular recordings in RT neurons after THC (3.5, 7, 10.5 mg/kg, i.v.). Results THC (2.5 and 5 mg/kg) treatment reversed mechanical allodynia between 1.5 and 4 hours after administration compared to VEH (p<0.05), reaching an antiallodynic plateau at 6 grams. Area- under-the curve analysis showed a significant increase after 2.5 (21.52 ± 0.33, p=0.01) and 5 (22.19 ± 0.87, p=0.004) mg/kg of THC versus VEH (16.12 ± 0.06). ECoG/EMG analyses indicated that NP rats spent less time in NREM sleep (−35%, p<0.05) and more time awake (+39.6%, p<0.05) than naïve rats. THC (5 mg/kg, i.p.) restored sleep–wake architecture by increasing NREM (205 ± 8.19) and reducing wake time (120 ± 10.43) (s), approaching values observed in non-neuropathic animals (NREM: 223.9 ± 11.4; wake: 102.0 ± 15.54). In RT pain-sensitive neurons, two response profiles were observed: (1) pain-inhibited neurons, in which THC (7 mg/kg, i.v.) increased firing rate (p=0.04); and (2) pain-excited neurons, in which THC (10.5 mg/kg, i.v.) decreased firing rate (p=0.009) versus baseline. Discussion & Conclusions Acute systemic THC dose-dependently reduced SNL-induced mechanical allodynia and normalized sleep–wake architecture in NP rats. These dual effects on pain and insomnia may be partially mediated by THC-dependent modulation of pain-responsive RT neuronal activity. THC therefore has potential therapeutic value for neuropathic pain with comorbid insomnia.