G protein-coupled receptors (GPCRs) comprise a large number of receptors. Orphan GPCRs are divided into six families. These groups contain orphan receptors for which the endogenous ligands are unclear. They have various physiological effects in the body and have the potential to be used in the treatment of different diseases. Considering their important role in the central and peripheral nervous system, their role in the treatment of pain has been the subject of some recent studies. At present, there are effective therapeutics for the treatment of pain including opioid medications and non-steroidal anti-inflammatory drugs. However, the side effects of these drugs and the risks of tolerance and dependence remain a major problem. In addition, neuropathic pain is a condition that does not respond to currently available analgesic medications well. In the present review article, we aimed to review the most recent findings regarding the role of orphan GPCRs in the treatment of pain. Accordingly, based on the preclinical findings, the role of GPR3, GPR7, GPR8, GPR18, GPR30, GPR35, GPR40, GPR55, GPR74, and GPR147 in the treatment of pain was discussed. The present study highlights the role of orphan GPCRs in the modulation of pain and implies that these receptors are potential new targets for finding better and more efficient therapeutics for the management of pain particularly neuropathic pain.
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