From the Guidelines
The stimulation of the periaqueductal gray/periventricular gray (PAG/PVG) system works to relieve pain primarily through activation of the endogenous opioid system. This is based on the understanding that brain regions regulating pain perception, including the periaqueductal gray, contain high levels of mu opioid receptors (MORs) 1. When the PAG/PVG system is stimulated, it triggers the release of endogenous opioids such as endorphins and enkephalins, which bind to opioid receptors throughout the descending pain modulatory pathway. This activation initiates a cascade that inhibits pain transmission at multiple levels of the nervous system. The PAG connects to the rostral ventromedial medulla, which then sends inhibitory signals down the spinal cord to suppress incoming pain signals.
Key points about the mechanism include:
- The role of mu opioid receptors in mediating analgesic effects, as they are highly expressed in brain regions associated with pain perception 1.
- The release of endogenous opioids upon stimulation of the PAG/PVG system, which contributes to the analgesic effect by binding to opioid receptors.
- The connection between the PAG and other parts of the brain involved in pain modulation, such as the rostral ventromedial medulla, which plays a crucial role in sending inhibitory signals to the spinal cord to suppress pain.
The evidence from the study on the use and misuse of opioids in chronic pain 1 highlights the importance of the opioid system in pain management and supports the notion that stimulation of the PAG/PVG system leverages this natural pain control circuit to produce analgesia. This mechanism is crucial for understanding how interventions like deep brain stimulation can provide relief in cases of intractable pain by amplifying the body's innate pain-relieving mechanisms.
From the Research
Mechanism of Pain Relief by PAG/PVG Stimulation
The mechanism by which stimulation of the PAG/PVG system works to relieve pain is not entirely clear, but several studies have investigated this topic.
- Increased release of GABA is not mentioned in the provided studies as a primary mechanism for pain relief by PAG/PVG stimulation.
- Activation of the endogenous opioid system is a possible mechanism, but a study from 2 suggests that pain relief elicited by PAG/PVG stimulation does not depend on an endogenous opioid mechanism in most patients.
- Activation of the endogenous cannabinoid system is not mentioned in the provided studies as a mechanism for pain relief by PAG/PVG stimulation.
- Increased release of glycine is not mentioned in the provided studies as a mechanism for pain relief by PAG/PVG stimulation.
Alternative Mechanisms
Other studies suggest that the endogenous opioid system plays a role in pain modulation, but the specific mechanism of PAG/PVG stimulation may involve other non-opioid mechanisms 2.
- The endogenous opioid system consists of widely scattered neurons that produce three opioids: beta-endorphin, the met- and leu-enkephalins, and the dynorphins, which act as neurotransmitters and neuromodulators at three major classes of receptors 3.
- The descending pain modulatory circuit, which includes the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM), is involved in pain modulation and may be affected by PAG/PVG stimulation 4.
- Alterations in endogenous opioid systems have been implicated in pain and opioid use disorder, highlighting the complexity of pain regulation and the need for further research 5.
Clinical Implications
The use of deep brain stimulation, including PAG/PVG stimulation, for the treatment of chronic pain has been explored in clinical practice 6.
- Stimulation of the PVG-PAG is mostly used in cases of nociceptive pain, while stimulation of the somatosensory thalamic nuclei (VPL-VPM) is almost exclusively used for the treatment of deafferentation pain.
- The success rate of PAG/PVG stimulation for pain relief varies, and the mechanisms by which electrical stimulation suppresses pain remain to be elucidated 6.