RT Journal Article
SR Electronic
T1 Modulation of Peripheral <em>μ</em>-Opioid Analgesia by <em>σ</em><sub>1</sub> Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 32
OP 45
DO 10.1124/jpet.113.208272
VO 348
IS 1
A1 Cristina Sánchez-Fernández
A1 Ángeles Montilla-García
A1 Rafael González-Cano
A1 Francisco Rafael Nieto
A1 Lucía Romero
A1 Antonia Artacho-Cordón
A1 Rosa Montes
A1 Begoña Fernández-Pastor
A1 Manuel Merlos
A1 José Manuel Baeyens
A1 José Manuel Entrena
A1 Enrique José Cobos
YR 2014
UL http://jpet.aspetjournals.org/content/348/1/32.abstract
AB We evaluated the effects of σ1-receptor inhibition on μ-opioid–induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several μ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral μ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated μ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The μ-opioid antinociception potentiated by σ1 inhibition (by σ1-receptor knockout or σ1-pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and σ1 receptor cannot account for our results, since the former lacked affinity for σ1 receptors (labeled with [3H](+)-pentazocine). A peripheral role for σ1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, σ1-receptor inhibition did not alter fentanyl- or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, σ1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral μ-opioid analgesia without affecting opioid-induced constipation.