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

Abstract

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

“…Such compounds include (+)-pentazocine, (+)-SKF10,047, SA4503 (1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine), and PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate) [14]. Since the Sig-1R ligand PRE-084 shows various activities in the central nervous system in animal models, such as nootropic and antidepressant activities [43], we included this compound in some of the flux assays as control. Interestingly, we found that PRE-084 also promotes autophagic activity in HeLa cells; PRE-084 induces the autophagic flux comparable to ANAVEX2-73: at 1 μM an over 1,5-fold induction of the autophagic flux was observed (Figure 1B).…”

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

“…In a series of studies of the effects on mechanical allodynia of Sig-1R agonists under control conditions and with pretreatment with capsaicin, Entrena et al (31,33) found that Sig-1R agonists did not alter sensitivity to mechanical stimulation under baseline conditions, and mechanical allodynia was present only when the system was pretreated with capsaicin. These effects were reversed by Sig-1R antagonists and absent in Sig-1R-knockout mice.…”

“…Antagonism of Sig-1R. Given that Sig-1R has been associated with capsaicin-induced mechanical hypersensitivity (31,33), we first tested whether these effects, which had not been directly linked to changes in TRPV1 activity or expression, can be explained by a role of Sig-1R on TRPV1-mediated pain processes.…”

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation

“…S1R is reported in the trigeminal ganglia of male mice (Yoon et al, 2015), but expression in female trigeminal sensory neurons currently unknown. Activation of S1R elicits nociceptive responses, which can be reversed with SR1 antagonists (Kim et al, 2008;Gris et al, 2014;Parenti et al, 2014;Pyun et al, 2014;Roh and Yoon, 2014;Tejada et al, 2014;Entrena et al, 2016) or in S1R knockout mice (Entrena et al, 2009;de la Puente et al, 2009). Progesterone is a potent S1R antagonist (Johannessen et al, 2011;Zamanillo et al, 2013) and can inhibit nociception (Maurice et al, 2001;Ueda et al, 2001;Maurice and Su, 2009).…”