Descending modulation of pain: the GABA disinhibition hypothesis of analgesia

•Descending pathways play a critical role in the central modulation of pain.•A particular descending PAG–RVM pathway mediates the phenomenon of stress-induced analgesia.•Opioids and cannabinoids are proposed to activate this system via a process of GABA disinhibition.•Recent evidence has emerged which conflicts with the GABA disinhibition hypothesis.•Alternative models have been proposed to account for descending analgesia.

Within the central nervous system, descending systems exist to endogenously modulate our perception of pain. Of particular interest is a descending pathway which projects via the midbrain periaqueductal grey (PAG) and rostral ventromedial medulla (RVM) to inhibit ascending nociceptive transmission at the spinal cord dorsal horn. This descending PAG–RVM system forms the circuitry that underlies the physiological phenomenon of stress-induced analgesia (SIA), which is mediated by parallel opioid and cannabinoid neurotransmitter systems in the PAG. At the cellular level, opioids and cannabinoids are hypothesised to activate descending analgesia through an indirect process of ‘GABA disinhibition’ — suppression of inhibitory GABAergic inputs onto output neurons which constitute the descending analgesic pathway. While there is much indirect evidence to support disinhibition, there are still questions regarding this model that remain unaddressed. Furthermore, there is growing evidence suggesting more complex models than originally proposed.