Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: Studies with selective sigma-1 ligands and sigma-1 knockout mice

Abstract

We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. This indicates that sigma(1) gene inactivation does not modify the perception of punctate mechanical stimuli. The intraplantar (i.pl.) administration of capsaicin induced dose-dependent mechanical allodynia in wild-type mice (markedly reducing both the threshold force necessary to induce paw withdrawal and the latency to paw withdrawal induced by a given force). In contrast, capsaicin was completely unable to induce mechanical hypersensitivity in sigma(1)-KO mice. The high-affinity and selective sigma(1) antagonists BD-1063, BD-1047 and NE-100, administered subcutaneously (s.c.), dose-dependently inhibited mechanical allodynia induced by capsaicin (1 microg,i.pl.), yielding ED(50) (mg/kg) values of 15.80+/-0.93, 29.31+/-1.65 and 40.74+/-7.20, respectively. The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.

Fat location defines sensation

“…In this way, despite the known mechanoinsensitivity of TRPV1, presynaptic amplification of nociceptive input through this receptor contributes to allodynia. Highdose peripheral capsaicin, which causes a sustained depolarization of peptidergic neurons, can cause allodynia, consistent with the present model (21). Pain research (with drugs in mind) has focused on mediators, rather than neuronal pathways, and we have limited insight into the innervation of dorsal horn neurons above a simple lamina specificity.…”

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

“…Inhibition of s 1 -receptor function either by the systemic administration of s 1 antagonists or by s 1 -receptor knockdown does not influence acute nociception per se (Cendán et al, 2005;De la Puente et al, 2009;Entrena et al, 2009b;Nieto et al, 2012;Romero et al, 2012;Sánchez-Fernández et al, 2013). However, s 1 inhibition is able to enhance opioid signaling (Kim et al, 2010) and to potentiate the antinociceptive effect of systemic opioids Pasternak, 1993, 1994;Marrazzo et al, 2011;Sánchez-Fernández et al, 2013;Vidal-Torres et al, 2013).…”

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

“…18,19 The role of σ 1 receptors in somatic pain control is well documented. Thus, σ 1 receptor knockout (σ 1 -KO) mice [20][21][22] and wild-type (WT) mice treated with σ 1 receptor antagonists [22][23][24][25][26][27][28][29] showed a marked reduction of pain-related behaviors in different models of somatic pain. However, it is not known whether σ 1 receptors also play a role in models of pure visceral pain.…”