Sigma-1 receptor antagonism as opioid adjuvant strategy: Enhancement of opioid antinociception without increasing adverse effects

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

“…We now extend those results by showing that this s 1 antagonist as well as BD-1063 enhance opioid antinociception against a different type of nociceptive (mechanical) stimulus, and more importantly, that the enhanced antinociception is mediated peripherally (see below). Moreover, we show that opioid-induced mechanical antinociception is clearly potentiated in s 1 -KO mice, which contrasts with the previously reported absence of modulation of opioid thermal antinociception in s 1 -KO mice (Díaz et al, 2009;Vidal-Torres et al, 2013). These apparently contradictory results seem to be related to the type of sensory stimulation used, and may be attributable to the known differences in the neurochemical mechanisms of thermal and mechanical opioid antinociception (Kuraishi et al, 1985;Wegert et al, 1997).…”

“…However, since most of the analgesia from systemic opioids is produced normally at central sites, it seems difficult to dissociate antinociceptive effects from centrally induced side effects. In this regard, we previously reported that despite the potentiation of antinociception by s 1 inhibition, the central side effects of morphine (e.g., hyperlocomotion, physical dependence, or mydriasis) were not altered (Sánchez-Fernández et al, 2013;Vidal-Torres et al, 2013). Here we show that the enhancement of opioid antinociception by systemic s 1 inhibition occurs primarily at peripheral levels, which might explain the lack of potentiation of morphine-induced central side effects.…”

“…We recently showed that although morphine-induced antinociception was potentiated in s 1 -KO mice, morphine-induced constipation remained unaltered (Sánchez-Fernández et al, 2013;Vidal-Torres et al, 2013). However, it is unknown whether these differential effects of s 1 inhibition also occur with other m opioids.…”

“…Hence, it is important to test whether the widely reported enhancement of morphine antinociception by s 1 inhibition (Chien and Pasternak 1993;Mei and Pasternak 2007;Díaz et al, 2009;Sánchez-Fernández et al, 2013) also occurs with other clinically relevant m opioids. It was recently reported that the systemic (subcutaneous) administration of S1RA enhanced antinociception against a thermal stimulus induced by morphine and other systemically administered centrally penetrant m-opioid analgesics (fentanyl, oxycodone, buprenorphine, and tramadol) (Vidal-Torres et al, 2013). We now extend those results by showing that this s 1 antagonist as well as BD-1063 enhance opioid antinociception against a different type of nociceptive (mechanical) stimulus, and more importantly, that the enhanced antinociception is mediated peripherally (see below).…”

“…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). Opioid antinociception can be potentiated by central s 1 inhibition (King et al, 1997;Pan et al, 1998;Pasternak, 2002, 2007;Marrazzo et al, 2006), and we recently reported that the local peripheral coadministration of s 1 antagonists and morphine also resulted in markedly enhanced antinociception (Sánchez-Fernández et al, 2013).…”