Effect and safety of listening to music or audiobooks as a coadjuvant treatment for chronic pain patients under opioid treatment: a study protocol for an open-label, parallel-group, randomised, controlled, proof-of-concept clinical trial in a tertiary hospital in the Barcelona South Metropolitan area.

BACKGROUND: Chronic non-cancer pain (CNCP) treatment's primary goal is to maintain physical and mental functioning while improving quality of life. Opioid use in CNCP patients has increased in recent years, and non-pharmacological interventions such as music listening have been proposed to counter it. Unlike other auditive stimuli, music can activate emotional-regulating and reward-regulating circuits, making it a potential tool to modulate attentional processes and regulate mood. This study's primary objective is to provide the first evidence on the distinct (separate) effects of music listening as a coadjuvant maintenance analgesic treatment in CNCP patients undergoing opioid analgesia. METHODS AND ANALYSIS: This will be a single-centre, phase II, open-label, parallel-group, proof-of-concept randomised clinical trial with CNCP patients under a minimum 4-week regular opioid treatment. We plan to include 70 consecutive patients, which will be randomised (1:1) to either the experimental group (active music listening) or the control group (active audiobooks listening). During 28 days, both groups will listen daily (for at least 30 min and up to 1 hour) to preset playlists tailored to individual preferences.Pain intensity scores at each visit, the changes (differences) from baseline and the proportions of responders according to various definitions based on pain intensity differences will be described and compared between study arms. We will apply longitudinal data assessment methods (mixed generalised linear models) taking the patient as a cluster to assess and compare the endpoints' evolution. We will also use the mediation analysis framework to adjust for the effects of additional therapeutic measures and obtain estimates of effect with a causal interpretation. ETHICS AND DISSEMINATION: The study protocol has been reviewed, and ethics approval has been obtained from the Bellvitge University Hospital Institutional Review Board, L'Hospitalet de Llobregat, Barcelona, Spain. The results from this study will be actively disseminated through manuscript publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05726266.

L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy.

Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.

Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Hippocampus: Cannabidiol Blunts Δ9-Tetrahydrocannabinol-Induced Cognitive Impairment.

At present, clinical interest in the plant-derived cannabinoid compound cannabidiol (CBD) is rising exponentially, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) that hinder clinical development of cannabis-based therapies. Despite this attention, the mechanisms of CBD action and its interaction with Δ9-THC are still not completely elucidated. Here, by combining in vivo and complementary molecular techniques, we demonstrate for the first time that CBD blunts the Δ9-THC-induced cognitive impairment in an adenosine A2A receptor (A2AR)-dependent manner. Furthermore, we reveal the existence of A2AR and cannabinoid CB1 receptor (CB1R) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent A2AR-CB1R functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal A2AR/CB1R complexes, nor anxiety responses related to other brain regions. Overall, these data provide new evidence regarding the mechanisms of action of CBD and the nature of A2AR-CB1R interactions in the brain.