CNS Pain Modulation Definition

The central modulation of pain perception is the result of electrical or pharmacological stimulation of certain regions of the midbrain. This analgesic effect arises from activation of descending pain-modulating pathways that project, via the medulla, to neurons in the dorsal horn that control the ascending information in the nociceptive system. The major brainstem regions that produce this effect are located in poorly defined nuclei in the periaqueductal gray matter and the rostral medulla.⁹⁰Purves D et al. The Physiological Basis of Pain Modulation – Neuroscience, 2nd edition. 2001. p1

Gate control theory of pain

In a landmark paper (1965), Patrick Wall and Ronald Melzack proposed the gate control theory of pain (GCT). Since then, it has proven to be a powerful tool for guiding pain research. GCT proposes that nociceptive and non-nociceptive signals are summated within the spinal cord and suggests that large nerves conduct non-nociceptive information and that smaller fibers conduct nociceptive information. If nociceptive signals outweigh non-nociceptive signals, a pain signal is propagated. Wall and Melzack also proposed that descending afferent fibers could modulate pain signals within the spinal cord.⁹¹Kirkpatrick DR et al. Therapeutic Basis of Clinical Pain Modulation. CTS vol 8, issue 6, 11 May 2015, p848.

Implicit in the Gate Control Hypothesis is the idea that pain is evoked when brain activity reaches a certain level due to sensory and/or central inputs. Melzack has expanded this idea into the Neuromatrix concept which for pain is a neural network with somatosensory, limbic and cognitive components. As in the Gate model, the output or “neurosignature” of the neuromatrix determining the painfulness of a sensory input is modulated by sensory input and differs in different individuals according to genotype and experiential variables. Thus the pain experience is not unique and can differ according to the individual as well as the injury. Another prediction of the Gate Control Hypothesis was that enhancing input selectively in large fibers would shut the Gate by reducing activity in T- cells; this would diminish any ongoing pain.⁹²Mendell LM. Constructing and Deconstructing the Gate Theory of Pain. Pain. 2014. p6

Descending pain modulation

Brainstem modulatory systems play a major role in pain facilitation.⁹³Porreca F, Ossipov M H, Gebhart G F 2002 Chronic pain and medullary descending facilitation. Trends in Neurosciences. p319. Inhibitory influences arising from the brain that descend in the spinal cord to modulate spinal reflexes. The PAG receives projections from a number of brain regions, including the amygdala, frontal and insular cortex, and hypothalamus, and acts in concert with the rostral ventromedial medulla (RVM) to provide a descending pain modulatory system. In addition to direct neural connections, endorphins synthesized in the pituitary are released into the cerebrospinal fluid and blood, where they can exert an inhibitory effect at several centers, including the PAG. Descending inhibition may be activated by external factors such as stress (stressinduced analgesia) and noxious input (diffuse noxious inhibitory controls), or can be induced by peripheral or central nervous stimulation.⁹⁴Hudspith MJ, Siddall PJ, Munglani R. Physiology of pain. In: Hemming HC, Hopkins PM, eds. Foundations of Anesthesia. 2nd ed. London, UK: Mosby; 2006. p281.

Anatomical, electrophysiological and pharmacological evidence has established that stimulation of the rostroventromedial medulla (RVM) can inhibit and/or facilitate nociceptive and non-nociceptive input in descending modulation of nociception, including that elicited by periaqueductal gray (PAG) stimulation.⁹⁵Porreca F, Ossipov M H, Gebhart G F 2002 Chronic pain and medullary descending facilitation. Trends in Neurosciences. p319

On and off cells in the RVM cells respond to manipulations of the periaqueductal gray PAG to produce behavioral analgesia by exerting a net inhibitory effect on nociception.⁹⁶Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. Wall & Melzack’s Textbook of Pain, 5th edition, P 130.

Opioid receptors are distributed throughout the pain-modulating circuit and exert a modulatory effect on nociceptive input.⁹⁷ Hudspith MJ, Siddall PJ, Munglani R. Physiology of pain. In: Hemming HC, Hopkins PM, eds. Foundations of Anesthesia. 2nd ed. London, UK: Mosby; 2006. p281.

The release of endogenous opioid ligands at spinal sites can produce an analgesic effect. These substances function in part by reducing transmitter release from the dorsal horn terminals of primary afferent nociceptors. They also direct postsynaptic inhibition of central neurons that are activated by noxious stimulation. Both (μ) mu and (δ) delta opioid receptor agonists block excitatory amino acid release from primary afferents. Endogenous opioids also contribute to pain modulation by inhibiting neuropeptide release from primary afferents.⁹⁸Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. Wall & Melzack’s Textbook of Pain, 5th edition, P 128.

Ascending pain modulation

Primary ascending pain reach from peripheral sites’ fibers to the dorsal horn of the spinal cord to innervate certain nociceptor neurons. Activation of opiate receptors at the spinal level produces hyperpolarization of the neurons, which result in the inhibition of firing and the release of substance P, a neurotransmitter involved in pain transmission, thereby blocking pain transmission. Opiate receptors at different CNS levels are target sites for neurotransmitters and endogenous opiates such as the endorphins and enkephalins. Binding at the receptors in subcortical sites leads to a change in the electrophysiological properties of these neurons and modulation of the ascending pain information.⁹⁹Dafeny N. Pain Modulation and Mechanisms Section 2, Chapter 8 Neuroscience Online. U of Texas. 1997. p3

Pain-modulating circuits

Such pain-modulating circuits offer the promise of rationally developed treatments based on manipulation of psychological variables, counterirritation, and new, more selective drugs or drug combinations.¹⁰⁰Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. Wall & Melzack’s Textbook of Pain, 5th edition, p125.