Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain

Figures & data

Table 1 ET receptor agonists and antagonists commonly used in basic research and clinical studies

Receptor	Agonists	Antagonists
ETA receptor	ET-1	BQ-123, atrasentan, SB234551, ABT-627, FR139317, A-127722.5, YM598
ETB receptor	ET-1, ET-2, ET-3, IRL-1620, sarafotoxin S6c	BQ-788, A-192621
ETA/ETB receptors	ET-1, ET-2, ET-3	Bosentan

Notes: ET-1 is listed as the only available agonist for the ET_A receptor. ET-2 and ET-3 will bind to the ET_A receptor, but they are not listed as ET_A agonists, as they have a 100-fold greater binding affinity for the ET_B receptor.²⁶ ET-1, ET-2, and ET-3 all have equal affinity for the ET_B receptor. IRL-1620 and sarafotoxin S6c bind exclusively to ET_B receptors. Several antagonists are listed for both receptors that are known to bind selectively to the receptor listed. Bosentan is the only known antagonist that has equal affinity for both the ET_A and ET_B receptors.

Abbreviation: ET, endothelin-1.

Figure 1 A schematic of the location of endothelin-1 (ET-1) and endothelin receptors found throughout the pain pathway.

Notes: ET_A receptor (ETAR) and ET_B receptor (ETBR) show different patterns of expression within the nervous system. Four areas are shown in detail in which ET receptors are known to be expressed on different cell types. (A) ET-1 mRNA and ETARs are found in several areas of the brain. ET-1 mRNA is found in the hippocampus, amygdala, hypothalamus, raphe nucleus, locus coeruleus, cerebral cortex, pontine tegmentum, and lateral reticular formation. The ETAR is also found in the hypothalamus, locus coeruleus, pontine tegmentum, and reticular formation, as well as the substantia nigra. (B) In the spinal cord, ET-1 immunoreactivity has been localized to laminae 1-V. The expression of ET_A and ETBRs within the spinal cord laminae has thus far not been investigated. (C) In the dorsal root ganglion (DRG), ETAR immunoreactivity has been found on primary afferent sensory small and medium diameter neurons. ETBRs are localized on satellite cells and nonmyelinating Schwann cells. (D) Within the skin, ETARs are found on peripheral nerve endings in small- and medium-diameter neurons. ETBRs are found on endothelial cells, smooth muscle, and keratinocytes.
Abbreviation: ET, endothelin-1.

Table 2 Effect of endothelin-1 administration in humans

Route of administration	Dose	Symptoms	Reference
Intraarterial	High	Vomiting, sweating, deep muscular pain	^Citation5
Intradermal	Moderate	Intense itching, erythema, increased sensitivity to mechanical stimuli, pressure tenderness	^Citation46
Intradermal	Low	Spontaneous pain, increased sensitivity to mechanical stimuli, cold hyperalgesia	^Citation49
Intracutaneous	Low	Burning and stinging pain, itching	^Citation51

Notes: Defined doses: high, >60 μg; moderate, 1–59 μg; and low, <0.9 μg.

Figure 2 Mechanisms of the endothelin system in various parts of the pain pathway at the cellular level in rodents.

Notes: (A) Endothelin-1 (ET_A) receptors located on nociceptors located in the skin mediate nociception; however, ET_B receptors located on keratinocytes mediate antinociception by causing the release of β-endorphin from keratinocytes, which activate opioid receptors on nociceptors, thereby decreasing the signal. (B) When a sensory neuron is stimulated by capsaicin and ET-1, ET_A receptors activate protein kinase C, which causes the phosphorylation of transient receptor potential vanilloid subfamily channels, thereby allowing cations to flow through the channel, causing potentiation of the signal. (C) Intrathecal administration of ET-1 causes the activation of L-type Ca²⁺ channels and the release of endogenous opioids, thereby causing analgesia. (D) ET-1 administration into the PAG produces analgesia via the ET_A and ET_B receptors and is dependent on N-methyl-D-aspartate activation. An intracerebroventricular injection of ET-1 also elicits analgesia; this is mediated by the ET_A receptor and α1 adrenergic receptor and antagonized by the ET_B receptor.
Abbreviations: CNS, central nervous system; TRPV1, transient receptor potential vanilloid subfamily; NMDA, N-methyl-D-aspartate; PAG, periaqueductal gray; ET, endothelin-1.

Table 3 Participation of ET_A and ET_B receptors in different models

Model	ETA receptor	ETB receptor	References
Exogenous application of ET-1
Spontaneous hind paw flinching	Pronociceptive	Antinociceptive	^Citation50,Citation59,Citation61
Abdominal constriction	Pronociceptive	Not tested	^Citation47,Citation48,Citation114
Sciatic nerve application	Pronociceptive	Little response	^Citation55
Nerve recordings	Pronociceptive	Antinociceptive	^Citation50
Spontaneous licking	Pronociceptive	Not involved	^Citation58,Citation60
Mechanical hyperalgesia	Not involved	Pronociceptive	^Citation46,Citation65,Citation68
	Pronociceptive	Pronociceptive	^Citation67
Thermal hyperalgesia	Pronociceptive	Not involved	^Citation60
ET-1 + formalin	Phase I: mediates	Phase I: not involved	^Citation52
	Phase II: mediates	Phase II: mediates
ET-1 + capsaicin licking	Pronociceptive	Not involved	^Citation75
Enhanced carrageenan paw elevation	Pronociceptive	Pronociceptive	^Citation92
No exogenous ET-1 application
Postsurgical mechanical hyperalgesia	Pronociceptive	Not tested	^Citation77
Phenylbenzoquinone-induced abdominal constriction	Not involved	Pronociceptive	^Citation146
Pruritus	Not involved	Pronociceptive	^Citation146
Inflammatory pain: thermal hyperalgesia	Pronociceptive	Not involved	^Citation67
Inflammatory pain: mechanical hyperalgesia	Pronociceptive	Pronociceptive	^Citation67
Primed inflammatory pain: paw elevation	Not involved	Pronociceptive	^Citation91
Cancer
Sarcoma virus infected	Early and late thermal hyperalgesia	Early thermal hyperalgesia	^Citation105
Sarcoma cells	Mediates nociception	–	^Citation147
Bone cancer	Nociception	Analgesia	^Citation102
Oral cancer	Increase in nociception and mechanical hyperalgesia via ETA	–	^Citation103
Skin cancer	Pronociceptive; mechanical allodynia	–	^Citation104
Oral cancer melanoma	Pronociceptive in oral cancer model		^Citation100

Abbreviation: ET, endothelin-1.

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