Inhibitory actions of endothelin-1 on pain processing.
Endothelin-1 (ET-1) in the central nervous system has been suggested to produce suppressive effects on pain transmission. We investigated the manner by which ET-1 exerts this action. ET-1 administered intracerebroventricularly produced a dose-dependent antinociceptive effect in a thermal pain test that utilized a spinal reflex to determine nociceptive thresholds. This suggested that the antinociceptive effect of ET-1 involved a descending pain inhibitory system. The antinociceptive effect was blocked by an ETA receptor antagonist but not by an ETB receptor antagonist, indicating that the action was mediated through the ETA receptor. Antagonists of opioid receptors, serotonin receptors, alpha-2 adrenergic receptors, oxytocin receptors, and dopamine receptors did not block the antinociceptive effect of ET-1. Thus, major descending inhibitory systems were probably not involved. The antinociceptive effect was blocked by intracerebroventricular administration of an alpha-1 adrenergic receptor antagonist. This indicated that the antinociceptive effect involved the activation of a supraspinal noradrenergic pathway, which in turn may activate a still unknown descending pain inhibitory system.
Available from: Terika Smith
- "Administration of ET-1 into the periaqueductal gray (PAG) of mice produces thermal analgesia mediated by both the ETA and ETB receptors and dependent on N-methyl-D-aspartate activation (Figure 2).53,81 Intracerebroventricular ET-1 dose-dependently produces analgesia to thermal stimuli,82 which is mediated by the ETA receptor and the α1 adrenergic receptor and antagonized by the ETB receptor (Figure 2).82 Thus, ET-1’s analgesic actions in the brain may be mediated via ETA and ETB receptors through a noradrenergic pathway that activates a descending inhibitory pathway to the spinal cord, possibly through the release of endogenous opioids. "
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ABSTRACT: Many people worldwide suffer from pain and a portion of these sufferers are diagnosed with a chronic pain condition. The management of chronic pain continues to be a challenge, and despite taking prescribed medication for pain, patients continue to have pain of moderate severity. Current pain therapies are often inadequate, with side effects that limit medication adherence. There is a need to identify novel therapeutic targets for the management of chronic pain. One potential candidate for the treatment of chronic pain is therapies aimed at modulating the vasoactive peptide endothelin-1. In addition to vasoactive properties, endothelin-1 has been implicated in pain transmission in both humans and animal models of nociception. Endothelin-1 directly activates nociceptors and potentiates the effect of other algogens, including capsaicin, formalin, and arachidonic acid. In addition, endothelin-1 has been shown to be involved in inflammatory pain, cancer pain, neuropathic pain, diabetic neuropathy, and pain associated with sickle cell disease. Therefore, endothelin-1 may prove a novel therapeutic target for the relief of many types of chronic pain.
Available from: Chi Wai Cheung
- "This provides a new insight into the current thoughts that ET-1 is antinociceptive in the CNS. We speculate that the level of ET-1 in the CNS may affect its actions on its receptors differently in pain modulation because the injected bolus of ET-1 produced analgesic effect as shown in previous studies [8, 14] while the endogenous level of ET-1 in the CNS did not exhibit such effect under pathological condition in our study because ETAR antagonist reduced pain sensation. "
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ABSTRACT: Endothelin-1 (ET-1) predominates in the endothelin family effectively in vascular tone control, mitogenesis, and neuromodulation. Its receptors are widespread in the central nervous system (CNS) associated with endogenous pain control, suggesting an important role of ET-1 in central pain processing. This study aimed to evaluate the effect of central ET-1 on the development of neuropathic pain behaviour by repeated intrathecal administration of endothelin type A receptor (ETAR) antagonist (BQ-123) in a sciatic nerve ligation (SNL) animal model. BQ-123 was administered intrathecally to rats at dosages 15 μ g, 20 μ g, 25 μ g, and 30 μ g, daily for 3 days. Mechanical allodynia was assessed daily 30 minutes before/after injection, 1 hour after injection of BQ-123 from post-SNL day 4 to day 6, and once on day 7 (without BQ-123 administration) before rats were sacrificed. Increasing trends of mechanical threshold were observed, and they reached significance at all dosages on post-SNL day 7 (P < 0.05 at dosage 15 μ g and P < 0.001 at dosages 20 μ g, 25 μ g, and 30 μ g) in comparison to control group. BQ-123 at dosage 30 μ g showed the most stable and significant mechanical threshold rise. Repeated central administration of BQ-123 alleviated mechanical allodynia after SNL. Our results provide insight into the therapeutic strategies, including timing, against neuropathic pain development with ETAR antagonist.
Available from: Kumiko Tanabe
- "Within the CNS, the distributions of these two receptors have been investigated in the endothelial cells of brain blood vessels, in neurons, and in glia (Khodorova et al., 2009; Schinelli, 2006). The intracerebroventricular endothelin-1-induced prolongation of paw-withdrawal latencies in the hot-plate test in mice is reportedly mediated through endothelin ET A receptors (Hasue et al., 2004). Additionally, intrathecal endothelin-1 depresses the flinching behavior elicited by plantar subcutaneous formaldehyde injection in rat through the endothelin ET A receptors (Yamamoto et al., 1994). "
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