Endothelins potentiate formalin-induced nociception and paw edema in mice

Abstract

The present study investigates the influence of endothelin (ET) related peptides (0.3-30 pmol/paw) on both phases of nociception and on edema induced by intraplantar injection of formalin (0.5% in 20 microL) in the mouse hind paw. The first phase of nociception (0-5 min after injection) was significantly potentiated by simultaneous injection of either ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selective ET3 receptor agonist sarafotoxin S6c (SRTX-c; up to 30 pmol/paw). All three peptides potentiated the second phase (10-30 min after injection) of formalin-induced nociception (at 3-30, 1-30, and 10-30 pmol/paw for ET-1, ET-3, and SRTX-c, respectively), whereas only ET-1 (10 or 30 pmol/paw) effectively enhanced edema caused by formalin (30 min after injection). Histamine also potentiated all three responses triggered by formalin, but was 30- to 100-fold less potent than ET-1. Treatment with the mixed ETA/ETB receptor antagonist bosentan (10 mg/kg i.p., 1 h beforehand) did not influence nociceptive and edematogenic responses to formalin or their potentiation by histamine (3 nmol/paw), but did inhibit the potentiations induced by ET-1 (10 pmol/paw). Thus, ET-1 potentiates formalin-induced nociception and edema in the mouse. These actions are possibly mediated via ETB and ETA receptors, respectively, but their true identity and the mechanisms involved still remain to be fully elucidated.

Interleukin-18 Induces Mechanical Hypernociception in Rats via Endothelin Acting on ETBReceptors in a Morphine-Sensitive Manner

“…Nevertheless, in the later phase of the overt nociception (inflammatory phase) or in mechanical hypernociceptive models, ET B mediates hypernociception. Reinforcing this hypothesis, there is evidence that ET-1, but jpet.aspetjournals.org not ET-3 and sarafotoxin S6c (ET B agonists), potentiate the first phase of formalin-induced flinches (immediate noninflammatory overt nociception), whereas ET-1, ET-3, and sarafotoxin S6c potentiate the second phase (inflammatory phase) of this test (Piovezan et al, 1997) and also induce long-lasting articular incapacitation in rats when injected in carrageenan-primed knee joints (De-Melo et al, 1998).…”

Tumor-Evoked Sensitization of C Nociceptors: A Role for Endothelin

“…Injection of ET-1 into the hind paw also produced tactile allodynia (Balonov et al 2006;McKelvy et al 2007), and mechanical (da Ferreira et al 1989) and heat (Menendez et al 2003b) hyperalgesia. Furthermore, local administration of ET-1 potentiated nocifensive behaviors evoked by intraplantar injection of capsaicin (Piovezan et al 1998) or formalin (Piovezan et al 1997;Yuyama et al 2004a) and intra-articular injection of an inflammatory evoking substance, carrageenan (Daher et al 2004;De-Melo et al 1998b), or prostaglandin E2 (Ferreira et al 1989). …”

Local Injection of Endothelin-1 Produces Pain-Like Behavior and Excitation of Nociceptors in Rats

“…The cause of this pain is unknown but may involve mediator-dependent signaling by tumor cells to spinal nerve roots. One candidate mediator, the potent vasoconstrictive peptide and mitogen endothelin-1 (ET-1), is secreted in high concentrations by metastatic prostate and breast cancer cells and is known to induce pain-like behavior in animals and pain in humans (Ferreira et al, 1989;Dahlof et al, 1990;Hammerman et al, 1997;Piovezan et al, 1997Piovezan et al, , 2000Carducci et al, 1998;Davar et al, 1998;De-Melo et al, 1998;GraidoGonzalez et al, 1998;Fareed et al, 2000;Jarvis et al, 2000). ET-1 is also found in high concentration in both dorsal root ganglion neurons (Giaid et al, 1989) and satellite cells (Kar et al, 1991), whereas endothelin-A (ET A ) receptors are found on small to medium sized dorsal root ganglion neurons and their axons (Pomonis et al, 2001), which is further evidence supporting a potential role for ET-1 in pain signaling.…”

“…In rodents, intraperitoneal administration of ET-1 produces pain behavior that is ET receptor-mediated (Raffa et al, 1996a,b), whereas intra-articular administration of ET-1 in dogs produces pain behavior and hyperalgesia (Ferreira et al, 1989). Similarly, in mice, intraplantar ET-1 potentiates pain states in models of chemical-and inflammation-induced pain (Piovezan et al, 1997;De-Melo et al, 1998). In humans, ET-1 injected into the brachial artery induced severe pain and prolonged, touch-evoked allodynia (Dahlof et al, 1990), and Carducci et al (1998) have reported that an endothelin-A receptor antagonist can reduce verbal reports of pain in patients with metastatic prostate cancer.…”