Inhibition or modulation are mechanisms which will change the pain experience. By modifying how the body reacts, the clinician will offer some relief to patients with chronic pain .

There are multiple mechanisms for pain modulation (inhibition and facilitation).  Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain.  Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus  and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers.


  • Gate control theory
    • In 1965, Ronald Melzack and Charles Patrick (Pat) Wall (Melzack and Wall 1965) proposed the Gate Control Theory of Pain.  They proposed that the gate in the spinal cord is the substantia gelatinosa in the dorsal horn, which modulates the transmission of sensory information from the primary afferent neurons to transmission cells in the spinal cord. This gating mechanism is controlled by the activity in the large and small fibers. Large-fiber activity inhibits (or closes) the gate, whereas small-fiber activity facilitates (or opens) the gate.
    • The mechanism of the gate is influenced both by descending nerves and peripheral input.
    • Examples of gate control in pain are rubbing a painful area or using a TENS unit.
  • Periaqueductal gray (midbrain) and Rostroventral medulla (PAG/RVM)
    • Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) and spinal cord dorsal horn, as a primary anatomical pathway mediating opioid-based analgesia.
    • The midbrain periaqueductal gray is a vital supraspinal site of the endogenous descending pain-modulating system.
    • The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors.
    • The PAG does not have a major projection to the spinal cord, and its role in the descending control seems to be exerted through pain modulating neurons located in the rostral ventromedial medulla (RVM), i.e. the nucleus raphe Magnus and adjacent structures.
    • Contributes with the release of inhibitory monoamines, serotonin and norepinephrine.
    • Main source of serotonin is nucleous raphe magnus.
    • Main source of norepinephrine is locus ceruleus.
    • Two types of RVM neurons have been shown to be involved in pain modulation, namely, off- and on-cells. Manipulations that cause off-cells to become continuously active and on-cells to become silent invariably produce analgesia.  Both off- and on-cells project to the dorsal horn.
    • PAG/RVM inhibits the release of excitatory neurotransmitters (CGRP and SP).
  • GABA/Glycine
    • GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels.
  • Reticular formation
    • The perception of pain is highly complex and requires neural integration from a variety of routes.
    • Spinal pathways to the amygdala, hypothalamus, reticular formation, medial thalamic nuclei, and limbic cortical structures transmit information involving arousal, bodily regulation, and emotional responses.
  • Conditioned modulation
    • Diminution of perceived pain intensity for a test stimulus following application of a conditioning stimulus to a remote area of the body, and is thought to reflect the descending inhibition of nociceptive signals.
  • Endogenous opioid system
    • Natural opioids are released in response to nociception (enkephalins, dynorphins and beta-endorphin).


  • Summation
    • Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity.
    • Spatial summation is a phenomenon in which repeated and equal-intensity noxious stimuli at a specific frequency cause an increase in the pain experienced.
  • Upregulation
    • Increase in the number or density of cell surface receptors for a physiologically active substance, causing an increase in sensitivity in response to persistent exposure.
  • Sodium channels upregulation means increased levels of transcription, subunit interaction or post-translational modification (notably glycosylation and phosphorylation).
  • Although several peripheral ion channels are involved in nociceptive transmission, it is obvious that voltage-gated sodium channels are the most important. Normally, sensory neurons are relatively quiet but following tissue injury, the number of voltage-gated sodium channels is upregulated at the peripheral terminals of nociceptors. This accumulation of sodium channels can lower the threshold for creating an action potential resulting in hyperexcitability of primary nociceptors (peripheral or nociceptor sensitization). And with ongoing nociceptive input to second-order neurons in the trigeminal brainstem, it can also result in central sensitization, an important mechanism involved in many chronic pain syndromes including neuropathic pain.


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