Cutaneous endothelin-A receptors elevate post-incisional pain

Abstract

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET A ), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Postincisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET A was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24 hr before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4 h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24 h, but that of secondary hyperesthesia remained strong for at least 24 h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24 h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET A in the immediate peri-operative period prevents the later development of central sensitization.

Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity

“…Cutaneous ATP has also been implicated in mechanical hypersensitivity that occurs in other elevated pain states that involve sensitization of nociceptive nerve endings, including inflammation and nerve injury [4; 6; 14; 26]. Our data suggest that endogenous ATP release could also contribute to pain under conditions of elevated ET-1, such as post-incision and inflammatory pain [25]. …”

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

“…*, significant difference from baseline (P Ͻ 0.001); #, significant differences from control mice (P Ͻ 0.001). 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).…”

“…Similarly BQ-788, but not BQ-123, blocked mechanical hyperalgesia produced by intraplantar injection of the proinflammatory cytokines interleukin 12 (Verri et al 2005) and interleukin 18 (Verri et al 2004). Postincisional pain may be due, at least in part, to inflammation and pretreatment of the skin with BQ-123 prior to the incision attenuates mechanical allodynia (Mujenda et al 2007). Thus ET A receptors contribute to mechanical allodynia and mechanical and heat hyperalgesia, whereas ET B receptors contribute only to mechanical hyperalgesia in these models of inflammation.…”

Participação da endotelina-1 na sinovite induzida por carragenina na articulação temporomandibular de ratos.

“…Por outro lado, concentrações menores (entre 10 pmols à ! alodinia mecânica (Balonov et al, 2006;Menendez et al, 2003;Piovezan et al, 1998 (Baamonde et al, 2004;Balonov et al, 2006), enquanto a dor evidente é inibida apenas pelo bloqueio do receptor ET A , da mesma forma que ocorre com todas as respostas pró-algésicas envolvendo ET 1 (Baamonde et al, 2004;Davar et al, 1998;De-Melo et al, 1998;;Gokin et al, 2001;Mckelvy et al, 2007;Mujenda et al, 2007;Raffa et al, 1996).…”

“…Khodorova et al (2006) (Baamonde et al, 2004;Davar et al, 1998;De-Melo et al, 1998;Gokin et al, 2001;Mckelvy et al, 2007;Mujenda et al, 2007;Raffa et al, 1996;).…”