# GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats
## 3 Discussion
Concordantly, GPR55 receptors in the dorsal root ganglion also raise intracellular calcium [8]. Studies in human embryonic kidney cells and DRG neurons show that GPR55-induced calcium increase is dependent on Gq and G12/13 proteins [8; 9; 23]. In this regard, the Gq protein pathway involves the activation of phospholipase C, and the subsequent opening of IP3-sensitive calcium channels and closing of voltage-gated potassium channels [8]. On the other hand, the recruitment of G12/13 by GPR55 activation promotes GTPase RhoA-mediated calcium mobilization from intracellular stores, which in turn stimulates the phosphorylation of mitogen-activated protein kinases (MAPK) and extracellular-regulated kinases (ERK) 1/2, as well as the induction of transcriptional factors, including nuclear-factor-activated T cells (NFAT), nuclear factor x\(\beta\) (NFx\(\beta\)), and cAMP response element-binding (CREB) proteins [8; 9; 23]. These transcriptional factors can translocate to the nucleus and regulate DNA transcription and gene expression. It has been reported that the activation of GPR55 receptors up-regulates mediators in neuropathic pain, such as interleukin (IL)-12, tumour necrosis factor (TNF)-\(\alpha\), interferon (IFN)- Y and granzyme B, among other proteins [24], and seems to regulate neuroprotective interleukins, such as IL-4 and IL-10 [14]. Interestingly, the GPR55 antagonist CID16020046 used in this study is associated with a reduction in phosphorylation of ERK1/2 [25], whereas the GPR55 agonist O-1602 increases intracellular calcium and ERK1/2 phosphorylation [20], which is in line with the signalling pathway reported for GPR55. It is worth emphasizing that the signalling mechanisms described for GPR55 here facilitate neuropathic pain processing. In addition, the LPI-mediated activation of GPR55 receptors increases the firing rate of low-threshold A\(\beta\) and nociceptive A\(\delta\) primary afferent fibres to mechanical stimuli [9]. In this regard, both types of fibres have been implicated in mechanical hyperalgesia, tactile allodynia and ectopic spontaneous activity since they are able to trigger and maintain an increased excitability of the spinal cord in neuropathic pain [26]. The administration of CID16020046 in the anterior cingulate cortex reduces the formalin-induced c-fos marker of neuronal activity in the spinal cord [25]. The localization and regulation of the GPR55 receptors also seems to support their nociceptive role. In our study, the GPR55 receptors were expressed in neurons of the dorsal horn of the spinal cord and dorsal root ganglia, as well as in glial cells of the spinal cord, satellite cells of the dorsal root ganglia and Schwann cells on the sciatic nerve, and this expression was not altered between naive and neuropathic rats. Correspondingly, other studies have confirmed that GPR55 receptors are expressed along the nociceptive pathway. Thus, at the peripheral level, GPR55 receptors are expressed in DRG neurons ([8; 13], this study), as well as in satellite glial cells ([13], this study) and Schwann cells [this study], two types of glia cells found in the peripheral nervous system whose activation after nerve injury participates in the development of neuropathic pain [27; 28]. In the central nervous system, GPR55 is also found in important areas for pain modulation, such as the thalamus, peri-aquetuclt gray and brainstem, among others [5; 10; 11; 12]. In addition, it has been reported in different pain types that GPR55 receptors increase nociception in the periaquetuclt gray [11; 15], anterior cingulate cortex [25], rostral ventromedial medulla [15] and spinal cord [this study]. To date, all studies indicate that GPR55 receptors up-regulate [12; 15; 29] or maintain their expression after some noxious stimuli ([30], this study). Taken together the data suggests that the receptors are necessary for the development and maintenance of neuropathic pain.