Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex‐different manner

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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (Bonica, 1979). Over many years, pain remains a significant problem in considerable patients. For several decades, analgesics such as opioids, nonsteroidal anti‐inflammatory drugs (NSAIDs), anesthetics, and antidepressants have been used to alleviate pain, but the curative effects are uneven, and unwanted or serious side effects are often unavoidable (Hayes et al., 2014). Therefore, it is of great importance to understand the pathophysiology underlying pain and find novel specific molecular targets for pain relief.
For a long time, the investigations of pain were performed in male animals. However, there are differences between sexes in clinical and experimental pain (Craft et al., 2004; Ring et al., 2009; Wiesenfeld‐Hallin, 2005). The differences between sexes could be found in various fields such as radicular pain (Tschugg et al., 2015), muscle pain (Yalinay Dikmen et al., 2015), cancer pain (Im et al., 2007), and so on. Females tend to perceive pain sooner and report greater pain than males, but the mechanism for this sex difference is unclear. Therefore, special antinociception methods for females are still rudimentary (Unruh, 1996).
Dopamine is a catecholamine neurotransmitter and plays a role in the pathology of human mental disorders like Parkinson disease (Olanow and Schapira, 2013), schizophrenia (Abi‐Dargham, 2014), and addiction (Le Foll et al., 2014). In recent years, researchers have revealed a central role of dopaminergic neurotransmission in pain modulation (Wood, 2008). A vital problem in understanding the dopamine system is to specify the functions of diverse dopamine receptors. The dopamine receptors belong to G protein–coupled receptors (GPCRs) including the D1‐like (D1 and D5) and D2‐like (D2–D4) families (Beaulieu and Gainetdinov, 2011). In particular, the dopamine D3 receptor has been demonstrated to play a role in nociception (Casarrubea et al., 2006; Potvin et al., 2009). And several studies have revealed that there are sex differences in the dopamine system. In rats, sex differences have been demonstrated for prefrontal cortical dopamine axon density and for the levels of dopamine together with turnover (Dalla et al., 2008; Kritzer and Creutz, 2008). In a clinical trial, female but not male rs4813625 C allele carriers showed greater stress‐induced dopamine release (Love et al., 2012).
In our present study, both male and female dopamine D3 receptor knockout (D3RKO) mice were employed to undergo the acute thermal pain modeled by hot‐plate test (HPT), mechanical pain modeled by von Frey hair test (VFHT), and persistent inflammatory pain modeled by formalin test (FT), to verify our hypothesis that the D3 receptor has effects on nociceptive regulation, particularly in a sex‐different manner. Wild‐type (WT) littermate mice were used as controls.
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