The Sigma 2 receptor promotes and the Sigma 1 receptor inhibits mu-opioid receptor-mediated antinociception
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RESEARCH
The Sigma 2 receptor promotes and the Sigma 1 receptor inhibits mu‑opioid receptor‑mediated antinociception Pilar Sánchez‑Blázquez1* , Elsa Cortés‑Montero1, María Rodríguez‑Muñoz1, Manuel Merlos2 and Javier Garzón‑Niño1
Abstract The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Glyol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neu‑ ropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies. Keywords: Sigma 2 receptor, Sigma 1 receptor, Knockout mice, Mu opioid receptor, Neuropathic pain, Analgesia Introduction Sigma receptors (σRs) are unique transmembrane proteins expressed throughout the central nervous system and in certain peripheral tissues. Based on current classifications, there are two types of these receptors, namely, the sigma-1 receptor (σ1R) and the sigma-2 receptor (σ2R) [1–4]. The σ1R was initially identified in 1976 as a member of the plasma membrane opioid receptor family [5], while σ2R was not discovered until later. For many years, σRs were described to bind to radioligands in preparations of brain synaptosomes. [3H]( +)-pentazocine *Correspondence: [email protected] 1 Neuropharmacology, Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Doctor Arce 37, 28002 Madrid, Spain Full list of author information is available at the end of the article
exhibits a high affinity for σ1R, whereas [3H]DTG binds with equal affinity to both σ1R and σ2R. Subsequent studies have revealed that these proteins are also involved in intracellular ion regulation and neuron survival [1, 4, 6–8]. The σ1R was purified, sequenced and cloned from guinea pig brain in 1996, and it bears little sequence homology to any known mammalian receptor [9]. On the other hand, it has been postulated that σ2R complexes with progesterone receptor membrane component 1 (PGRMC1). The rec
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