Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

Abstract

Background and Purpose We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N‐(4‐hydroxyphenyl)‐5Z,8Z,11Z,14Z‐eicosatetraenamide) to activate CB1 receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol‐induced analgesia remain unknown. Experimental Approach The effects of paracetamol on brain function in Sprague‐Dawley rats were determined by functional MRI. Levels of neurotransmitters in the periaqueductal grey (PAG) were measured using in vivo 1H‐NMR and microdialysis. Analgesic effects of paracetamol were assessed by behavioural tests and challenged with different inhibitors, administered systemically or microinjected in the PAG. Key Results Paracetamol decreased the connectivity of major brain structures involved in pain processing (insula, somatosensory cortex, amygdala, hypothalamus, and the PAG). This effect was particularly prominent in the PAG, where paracetamol, after conversion to AM404, (a) modulated neuronal activity and functional connectivity, (b) promoted GABA and glutamate release, and (c) activated a TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signalling cascade to exert its analgesic effects. Conclusions and Implications The elucidation of the mechanism of action of paracetamol as an analgesic paves the way for pharmacological innovations to improve the pharmacopoeia of analgesic agents.

Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study

“…The fact that neurological dysfunction underlies both sleep and attentional issues in children [ 40 ], suggests that an important mechanism of influence may be the impact of acetaminophen on prenatal neurology, which may impact the regulation of attention and sleep in the preschool period. On this note, acetaminophen has been found to be associated with reduced brain connectivity of the amygdala, a part of the brain responsible for self-regulation [ 41 ].…”

Pain Management - Practices, Novel Therapies and Bioactives

“…When patient has needle aversion or needle phobia Despite its prevalence, reported musculoskeletal pain is often under-diagnosed in adolescents [153,154]. Healthcare providers may be unfamiliar or not trained to diagnose chronic pain, muscle trigger points, palpable pain points, and fascia in tension [155][156][157][158]. Presenting symptoms such as neck pain, shoulder pain, abdominal pain and headaches do not immediately direct a physician to look for a myofascial component to pain.…”

“…Pain Management -Practices, Novel Therapies and Bioactives receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA -through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also potential substantial detrimental side effects of APAPs.…”

Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis

“…This could help to explain why APAP may not have significant clinical effect on conditions such as osteoarthritis (further details below; [153,154]). A recent study confirmed that APAPs act mainly on central analgesic pathways, showing that APAP modifies the activity and connectivity of analgesia via FAAH, activating a signalling cascade involving TRPV1 channels, mGlu5 receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA -through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also potential substantial detrimental side effects of APAPs.…”