Therapeutic Basis of Clinical Pain Modulation

Abstract

Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within the past 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this paper would be helpful in developing novel therapies, metrics, and interventions for improved patient management.

Keywords: Gate Control Theory; cannabinoids; electroanalgesia; inhibitory amino acids; opioids; pain modulation; periaqueductal gray; rostral ventromedial medulla.

Figure 1

Gate Control Theory. Both small and large fibers from the periphery come into the substantia gelatinosa. Generally, larger fibers carry general somatosensation information while smaller fibers carry nociceptive information. The two fiber types summate in the substantia gelatinosa. If the signal carried by the nociceptive fibers is stronger than the general sensation signal, a pain stimulus can be passed from the substantia gelatinosa toward the brain. Descending modulatory fibers interact with pain signals in the substantia gelatinosa.

Figure 2

Nociceptive signaling in the amygdala. Dopamine acts within the amygdala. Via K+ channels and D2‐like receptors, dopamine leads to decreased glutamate secretion. Glutamate activates group 1 metabotropic glutamate receptors, leading to the activation of G‐proteins, phospholipase C, cleaving of PIP₂ into DAG and IP₃, and the opening of intracellular calcium channels. Once open, calcium channels release calcium into amygdala cells, leading to a variety of excitatory effects that cause increased nociception.

Figure 3

Opioid inactivation of calcium channels. Opioids act on opioid receptors (μ, κ, δ, and opioid receptor‐like receptor [ORL]) leading to the activation of G‐proteins and both direct and indirect closing of ion channels. Activated G‐proteins can directly close ion channels. Activated G‐proteins also inactive adenylate cyclase, which, when activated, opens ion channels.

Figure 4

Schema for analgesia. This schematic diagram briefly illustrates the mechanism of analgesic action for a variety of modulatory processes. Starting from the top left and moving clockwise, the legend will briefly summarize each. Placebo modulation works via the endogenous opioid pathway. Endogenous opioids activate opioid receptors. The primary effect of activated opioid receptors is analgesia through inhibition of Ca⁺⁺ and K⁺ channels, thus preventing the release of neurotransmitter vesicles. Electrical stimulation provides analgesia by increasing competitive, somatosensory signals, resulting in less nociceptive transmission. Galanin works by decreasing nociceptive transmission via GalR1, 2, and 3 receptors. Cannabinoids work by inhibiting TRP channels (pain transduction) and by decreasing nociceptive transmission via alpha‐3 receptors. Cholecystokinin (CCK) receptor activation decreases GABA and antagonizes opioid and cannabinoid receptors. Antagonizing CCK receptors can have an analgesic effect. GABA is an inhibitory amino acid. Agonistic activity of GABA receptors can diminish the sensation of pain. Serotonin mediates analgesia via a variety of 5‐HT receptors. Norepinephrine mediates analgesia via alpha‐2 receptors. Dopamine inhibits glutamate release, which decreases pain transmission. Exogenous opioids work via the same receptors and processes as endogenous opioids.