title: Sigma-1 receptor antagonism as opioid adjuvant strategy: enhancement of opioid antinociception without increasing adverse effects.
abstract: While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.
authors: Esteve, Drug Discovery and Preclinical Development. Parc Científic de Barcelona. Carrer Baldiri Reixac, 4-8. 08028 Barcelona, Spain.
authors: Alba
authors: A
authors: Vidal-Torres
authors: Beatriz
authors: B
authors: de la Puente
authors: Maria
authors: M
authors: Rocasalbas
authors: Clara
authors: C
authors: Touriño
authors: Simona Andreea
authors: SA
authors: Bura
authors: Begoña
authors: B
authors: Fernández-Pastor
authors: Luz
authors: L
authors: Romero
authors: Xavier
authors: X
authors: Codony
authors: Daniel
authors: D
authors: Zamanillo
authors: Helmut
authors: H
authors: Buschmann
authors: Manuel
authors: M
authors: Merlos
authors: José Manuel
authors: JM
authors: Baeyens
authors: Rafael
authors: R
authors: Maldonado
authors: José Miguel
authors: JM
authors: Vela
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D003213:Conditioning, Psychological / Q000187:drug effects; D004357:Drug Synergism; D004361:Drug Tolerance; D005772:Gastrointestinal Transit / Q000187:drug effects; D055786:Gene Knockout Techniques; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D015878:Mydriasis / Q000139:chemically induced; D009270:Naloxone / Q000494:pharmacology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects; D000097605:Sigma-1 Receptor
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D009270:Naloxone; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor