Abstract
Morphine is a potent analgesic opiate commonly used in treating pain, and it is also a substance of abuse and highly addictive. Hence, it is vital to discover the action sites of morphine in the brain to increase its efficacy of treatment. In the present study, we aimed at identifying comprehensive neuroanatomical locations that are sensitive to morphine in the adult zebrafish (Danio rerio). We performed in situ hybridization to localize the mu opioid receptor (oprm1) gene and to map the morphine sensitive brain areas using neuronal PAS domain-containing protein 4a (npas4a), an early gene marker. Real-time PCR was used to detect changes in mRNA levels of oprm1 and npas4a in control and acute morphine treated fish (2 mg/L; 20 min). Intense positive oprm1 signals were seen in the telencephalon, preoptic area, habenula, hypothalamic area and periventricular gray zone of the optic tectum. Acute morphine exposure significantly increased oprm1 and npas4a mRNA levels in the medial zone of dorsal telencephalon (Dm), ventral region of the ventral telencephalon (Vv), preoptic area, and in the hypothalamus but a decrease in oprm1 and npas4a signals in the dorsal habenula. This study provides a detailed map of oprm1 localization in the brain, which includes previously unreported oprm1 in the habenula of teleost. Presence of oprm1 in multiple brain sites implies multiple action targets of morphine and potential brain functions which could include reward, cognitive and negative emotions.
Highlights
Morphine is a well-documented analgesic drug used to treat severe pain
We found specific cell populations that are sensitive to morphine
The wide distribution of oprm1 gene, as well as morphine-dependent expression of npas4a in the brain, indicate that morphine can act on multiple brain sites and neural circuits, which implies that morphine can potentially influence a variety of brain functions including reward, cognitive, and aversive functions in fish
Summary
In addition to its analgesic effect, morphine exerts its rewarding properties, which leads to opioid addiction. The multiple action sites of morphine in the brain decrease the effectiveness of morphine due to development of tolerance, physical dependence, and addiction. It primarily binds to MOR to exert its analgesic pharmacological properties (Corbett et al, 1993; Kieffer, 1999). In the brain of mammals, MOR are widely expressed in several areas including the periaqueductal gray, thalamus, cingulate cortex and the insula, which is involved in mediating pain signals (Kitchen et al, 1997; Le Merrer et al, 2009; Lutz and Kieffer, 2013; Cahill et al, 2014), while MOR in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) are involved in opiate-induced reward (Contet et al, 2004). Identifying the comprehensive distribution of MOR is important to elucidate the target sites and understanding of brain regions that are potentially affected by morphine
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