σ1Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

Abstract

Background: Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (σ 1 ) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored. Methods: The authors evaluated the role of σ 1 receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and σ 1 receptor knockout (σ 1 -KO) (n = 10 per group) mice, selective σ 1 receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen). Results: The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and σ 1 -KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in σ 1 -KO mice (mean ± SEM, 22 ± 2.9) was 48% of that observed in WT animals (46 ± 4.2). Subcutaneous administration of the σ 1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 ± 0.05 g) in WT mice. In contrast, these drugs produced no change in σ 1 -KO mice. Thus, the effects of these drugs are specifically mediated by σ 1 receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and σ 1 -KO mice, whereas ketoprofen had no effect in either mouse type. Conclusion: These results suggest that σ 1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value.

Investigational sigma-1 receptor antagonists for the treatment of pain

“…E-52862 dose-dependently reduced mechanical allodynia and thermal hyperalgesia in a model of postoperative pain in mice [111]. E-52862 also reduced the number of behavioral responses and reversed the referred hyperalgesia in a model of capsaicin-induced visceral pain [38]. This latter result raises novel perspectives for the treatment of visceral pain.…”

“…More recently, its enhancing effect on peripheral µ-opioid analgesia has been reported when combined with other opioids including fentanyl, oxycodone, buprenorphine, loperamide and tramadol [6]. When administered systemically alone, without opioids, BD-1063 inhibited mechanical allodynia induced by capsaicin in mice [17] and was active in mice models of different types of pain, such as chemotherapy-induced neuropathic pain (paclitaxel-induced painful neuropathy) [37] and visceral pain induced by intracolonic administration of capsaicin [38]. It also reversed mechanical (paw pressure) and thermal (radiant heat) carrageenaninduced inflammatory hyperalgesia in mice when administered systemically (subcutaneously) or at the inflammation site (intraplantarly) [39].…”

“…Additionally, it potentiated the antinociceptive effect of agmatine, an endogenous biogenic amine and NMDA receptor antagonist, in a rat sciatic nerve ligation neuropathic pain model [40]. NE-100 (3) was reported to potentiate morphine-induced mechanical antinociception when administered subcutaneously or intraplantarly [29] and to inhibit mechanical hypersensitivity induced by intraplantar injection of capsaicin [17] and intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) [38] when subcutaneously administered to mice in the absence of opioids.…”

Effects of Tetrodotoxin in Mouse Models of Visceral Pain

“…However, this neurotoxin, and in consequence the contribution of TTX-sensitive VGSCs to visceral pain, has never been investigated in a pure visceral pain model. In the present study, we have evaluated the antinociceptive effects of TTX in three different visceral pain models in mice: the intracolonic administration of both capsaicin [24,25] and mustard oil [26,27] and a model of cyclophosphamide-induced cystitis [27,28]. These models are viscero-specific and permit the examination of both visceral pain and referred mechanical hyperalgesia to the abdominal wall, with this latter feature being clinically very relevant and characteristic of visceral pain.…”

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

“…refs 8, 16 and 17), they are able to decrease the pain responses induced by chemical irritants such as formalin or capsaicin (e.g. refs 18, 19, 20) as well as the sensory gain (allodynia or hyperalgesia) occurring due to sensitization of the nociceptive system by capsaicin81621 or by pathological states such as neuropathy, inflammation or ischemic pain817222324.…”