Endothelin‐1‐induced ET_A receptor‐mediated nociception, hyperalgesia and oedema in the mouse hind‐paw: modulation by simultaneous ET_B receptor activation

Abstract

1 Endothelin-1 causes ET A receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic eect of endothelin-1 is also accompanied by other proin¯ammatory eects, namely nociception and oedema, and characterized the endothelin ET receptors involved. 2 Intraplantar (i.pl.) hind-paw injection of endothelin-1 (0.3 ± 30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20.5+3.3 s; endothelin-1 at 30 pmol, 78.1+9.8 s), largely con®ned to the ®rst 15 min. Endothelin-1 (1 ± 10 pmol) potentiated ipsilateral capsaicininduced (0.1 mg, i.pl.; at 30 min) nociception (vehicle, 40.2+2.6 s; endothelin-1 at 10 pmol, 98.4+5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+2.3 mg; endothelin-1 at 30 pmol, 100.3+6.1 mg). 3 Selective ET B receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. 4 ET A receptor antagonists BQ-123 (1 nmol, i.pl.) or A-127722-5 (6 mmol kg 71 , i.v.) prevented all eects of endothelin-1 (10 pmol), but the ET B receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineective. 5 BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic eects of 30 pmol endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. 6 Thus, endothelin-1 triggers ET A receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ET B receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, eects of the peptide.

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

“…1998a), injected subcutaneously into the plantar surface of the hind paw, (Baamonde et al 2004;Balonov et al 2006;Gokin et al 2001;Houck et al 2004;Menendez et al 2003b;Piovezan et al 1998Piovezan et al , 2004Verri et al 2004Verri et al , 2005 or skin of the back (Mujenda et al 2007), and injected into tumor-bearing tissues Schmidt et al 2007;Wacnik et al 2001). In contrast, the newer ET A receptor-selective antagonists have been administered systemically (Chichorro et al 2006a;Klass et al 2005;Matwyshyn et al 2006;Piovezan et al 2000;Trentin et al 2006). Because we were interested in the role of ET A receptors near the tumor, presumably on the terminals of C nociceptors, we chose BQ-123 as the ET A receptor-selective antagonist as it has been shown to be effective when injected into peripheral tissues.…”

“…For example, injection of ET-1 into the plantar surface of the hind paw evoked dose-dependent hind paw licking (Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000), and application of ET-1 directly to the sciatic nerve evoked robust hind paw flinching (Davar et al 1998;Fareed et al 2000). 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.…”

“…More recently, it has been reported that intradermal injection of ET-1 produced a short-lasting spontaneous pain and longer-lasting mechanical and cold hyperalgesia (Hans et al 2007;Namer et al 2007). The mechanisms by which injection of ET-1 into peripheral tissues evokes nocifensive behaviors and hyperalgesia to heat appears to be mediated through the ET A receptor as pretreatment with systemic (i.e., atrasentan or A-127722-5) or local (i.e., BQ-123) ET A receptor-selective antagonists or co-application of BQ-123 with ET-1, attenuated these effects (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000). In contrast, pretreatment with or co-application of ET B receptor-selective antagonists (e.g., BQ-788) did not attenuate the ET-1-evoked nocifensive behaviors or heat hyperalgesia (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Menendez et al 2003b;Piovezan et al 2000).…”

“…The mechanisms by which injection of ET-1 into peripheral tissues evokes nocifensive behaviors and hyperalgesia to heat appears to be mediated through the ET A receptor as pretreatment with systemic (i.e., atrasentan or A-127722-5) or local (i.e., BQ-123) ET A receptor-selective antagonists or co-application of BQ-123 with ET-1, attenuated these effects (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000). In contrast, pretreatment with or co-application of ET B receptor-selective antagonists (e.g., BQ-788) did not attenuate the ET-1-evoked nocifensive behaviors or heat hyperalgesia (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Menendez et al 2003b;Piovezan et al 2000). The potentiating effect of ET-1 on nocifensive behaviors evoked by capsaicin, formalin, or inflammation was also mediated through the ET A , but not ET B , receptor subtype (Daher et al 2004;Piovezan et al 1998;Yuyama et al 2004a).…”

“…Numerous studies have demonstrated that injection of ET-1 into the knee or hind paw evokes nocifensive behaviors (Baamonde et al 2004;Balonov et al 2006;De-Melo et al 1998a;Ferreira et al 1989;Gokin et al 2001;McKelvy et al 2007;Menendez et al 2003b;Piovezan et al 1998Piovezan et al , 2004Verri et al 2004Verri et al , 2005, tactile allodynia (Balonov et al 2006;McKelvy et al 2007), and mechanical (da Ferreira et al 1989) and heat (Menendez et al 2003b) hyperalgesia through a mechanism involving the ET A receptors located in peripheral tissues (Baamonde et al 2004;Davar et al 1998;De-Melo et al 1998a;Fareed et al 2000;Gokin et al 2001;Menendez et al 2003b;Piovezan et al 2000). Injection of ET-1 into the skin excites C nociceptors (Gokin et al 2001;Khodorova et al 2002;Namer et al 2007) and likely contributes to ET-1-evoked nocifensive behaviors.…”