# GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats
## 3 Discussion
Moreover, our results confirm pharmacologically the nociceptive role of GPR55 receptors in the maintenance of neuropathic pain, show their localization for the first time in Schwann cells and spinal cord, and evaluate their participation at spinal level. On the other hand, in the current study, the intrathecal administration of AS1269574, a GPR119 receptor agonist, produced an antillodyncit effect in L5-L6 spinal nerve ligation-submitted neuropathic rats. In line with our results, a study found that oleoylethanolamide decreases acetic acid- and formalin-induced pain through peroxisome-proliferative-activated receptors (PPAR), an \(\alpha\)-activation independent mechanism [31]. Although, the study might suggest the participation of GPR119 receptors in inflammatory and visceral pain, data should be interpreted with care because oleoylethanolamide could also act on TRPV1 [32], NMDA [31] and GPR55 [10] receptors. To date, there are no specific antagonists of GPR119, so we decided to administer a G-protein antagonist peptide (G-PP), which blocks the activation of G proteins by receptors in a reversible and competitive way [33]. In our study, G-PP was able to reverse the antillodyncit effect induced by AS1269574, at doses ineffective by themselves. Even though it has been reported that AS1269574 activates TRPA1 channels to stimulate glucagon-like peptide-1 in an independent manner to GPR119 activation [34], the antillodyncit effect of AS1269574 in this study seems to involve spinal GPR119 receptor activation since this effect was reversed by a G-protein antagonist and TRPA1 activation induces allodynia in nociceptive neurons [35]. Consistent with the behavioural results, we showed that GPR119 receptors are located in both neurons and glial cells of the spinal cord. Furthermore, they were expressed in DRG neurons, satellite cells and Schwann cells at the peripheral level, indicating their expression along the nociceptive pathway. In addition, the anti-neuropathic effect of GPR119 receptors in the spinal cord seems to be specific since spinal administration of AS1269574 (300 \(\mathrm{\SIUnitSymbolMicro g}\)) or G-PP (1 \(\mathrm{\SIUnitSymbol ng}\)) did not modify the plasmatic glucose levels or motor performance at the highest dose tested. Regarding their transduction mechanism, GPR119 receptors appear to be associated preferentially to G\(\alpha\)s proteins and elevation of cyclic adenosine monophosphate (cAMP) in transfected cells [36; 37], but they have been linked to G\(\alpha\)i and G\(\alpha\)q proteins as well [37]. Another group found that GPR119 agonists differ from one another in the G proteins activated [38], an observation that could be tissue specific since the coupling to G proteins for GPR55 receptors has only been studied using cell lines. According to our results, GPR119 receptors could be coupled to G proteins at spinal level because their stimulation hyperpolarizes neurons by opening of potassium channels and closing of calcium channels [39]. Accordingly, it has been reported that the administration of AS1269574, the GPR119 receptor agonist used in this study, inhibits the phosphorylation of \(\mathrm{\SIUnitSymbol IxB}\alpha\), JNK, and ERK [40]. Unlike GPR55 receptors, in our study, GPR119 receptors were downregulated in the spinal cord and sciatic nerve in rats submitted to spinal nerve injury. In line with our results, GPR119 transcripts are diminished in patients with intestinal inflammation [41]. Thus, the decrease of the GPR119 receptor expression in the face of noxious stimuli appears to be a regulatory mechanism that facilitates pain sensitization. In support of this view, it has been reported that some agonists desensitize GPR119 receptors after their activation [42]. This effect seems to be associated with the recruitment of \(\beta\)-arrestin [37], a small protein involved in the desensitization, internalization and recycling of G-protein-coupled receptors. To the best of our knowledge, this is the first study to evaluate the participation of GPR119 receptors in pain.