Activation of the Naloxone-sensitive Sigma Receptor by (+)-Morphine or (−)-Morphine Attenuates (−)-Morphine-induced Analgesia and Addiction

(−)-Morphine, but not (+)-morphine, interacts with μ-opioid receptors to produce antinociception (analgesia). The antinociception produced by (−)-morphine is attenuated by pretreatment with (+)-morphine or (−)-morphine given spinally, supraspinally, or systemically. This phenomenon has been defined as antianalgesia, which is induced by (+)-morphine or (−)-morphine against the (−)-morphine-induced antinociception following activation of the naloxone-sensitive σ receptors. In addition, (+)-morphine or (−)-morphine pretreatment attenuates the antinociception produced by δ-opioid receptor agonist deltorphin II or κ-opioid receptor agonist U50,488 H in μ-opioid receptor knockout mice. The antianalgesia induced by (+)-morphine or (−)-morphine against (−)-morphine-induced analgesia is mediated through activation of p38-mitogen-activated protein kinase. (−)-Morphine, but not (+)-morphine, induces the conditioned place preference, and the conditioned place preference induced by (−)-morphine is attenuated by pretreatment with (+)-morphine or (−)-morphine. Furthermore, (+)-morphine blocks the increase in the extracellular dopamine in the nucleus accumbens shell produced by μ-opioid agonist endomorphin-1 from the ventral tegmental area. These effects of (+)-morphine in attenuating the (−)-morphine-induced conditioned place preference and increased release of dopamine are also mediated through activating naloxone-sensitive σ receptors. In conclusion, the review article depicts the mechanisms involved in the acute antinociceptive (analgesic) tolerance to (−)-morphine and the attenuation of (−)-morphine-induced conditioned place preference (addiction) with (+)-morphine.