469. The serotonin 5-HT2A agonist psilocybin in the treatment of neuropathic pain

Abstract Background Pain conditions are major health problems resulting in physical, psychological and social impairment (1), and health care costs (2,3). Within the last decade, research has demonstrated that 5-HT2A agonists including psilocybin and LSD elicit spiritual experiences (4) and functional connectivity changes between diverse brain areas (5). Therefore, it is pertinent to investigate the anti-allodynic properties of psilocybin in a neuropathic pain (NP) model and understand its mechanism of action. Aims & Objectives The aim of this study is to investigate the anti-allodynic effect of psilocybin on SNL-induced NP and elucidate psilocybin’s mechanism of action underlying effects on emotional aspects of pain. The objectives of this study were to investigate whether psilocybin produces anti-allodynic effects in a rat model of NP, called Spinal Nerve Ligation (SNL) and to understand the mechanism of action of the anti-allodynic effects of psilocybin in brain areas associated with physiological and emotional aspects of NP using electrophysiological recordings in SNL- and sham-operated rats.

Method: Neuropathy was induced using SNL (L5/L6 ligation) in Wistar rats. Fifteen days later, baseline mechanical allodynia was assessed using von Frey (VF) filaments (6). NP rats were then divided into three experimental cohorts, and the following experiments were performed: a) Mechanical allodynia was evaluated every 30 min for 5 h using VF filaments following administration of vehicle (saline) or psilocybin (3 or 10 mg/kg, i.p.); b) In vivo single-unit electrophysiological recordings were conducted in the rostral ventromedial medulla (RVM) to assess ON (pronociceptive) and OFF (antinociceptive) cells, associated with nociceptive processing; c) In vivo single-unit electrophysiological recordings were conducted in glutamatergic neurons of the ACC, a brain region associated with the affective/emotional aspects of pain. For electrophysiology, once a cell was identified, escalating doses of psilocybin (1.5–10.5 mg/kg, i.v.) were administered at 5-min intervals.

Results: Psilocybin (3 or 10 mg/kg) did not significantly reverse mechanical allodynia during the 0–5 h period after administration compared with vehicle (all p>0.05), although a transient, non-significant reduction in allodynia was observed at 30 min and 1 h post-dose. Area-under-the-curve (AUC) analysis showed no significant differences for 3 mg/kg (14.88±5.72; p>0.999) or 10 mg/kg (21.27±3.63) versus vehicle (12.59±1.58; p=0.0748). Electrophysiological recordings from RVM neurons indicated that psilocybin did not affect the firing rate of ON-cells (F(7,70)=1.313; p=0.2572) or OFF-cells (F(7,63)=1.561; p=0.1638). In contrast, glutamatergic neurons in the ACC of NP rats exhibited a higher baseline firing rate (4.66±1.37) compared with naïve rats (1.53±0.54; p<0.05). In NP animals, psilocybin significantly decreased ACC glutamatergic neuron firing relative to baseline (4.66±1.37) at 3 mg/kg (0.41±0.23; p<0.01), 4.5 mg/kg (0.45±0.23; p<0.01), and 6 mg/kg (1.17±0.55; p<0.05). Discussion & Conclusions These results demonstrate that acute administration of psilocybin only transiently (30 minutes- 1hr) reverses spinal nerve ligation-induced mechanical allodynia and has not effects in ON/OFF neurons. However, psilocybin reduces and normalizes firing rate of excitatory glutamatergic neurons in the ACC, indicating that psilocybin’s effect on NP can be partially explained by its ability to modulate excitatory neurons in brain areas associated with emotional aspects of pain.