# GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats
## 3 Discussion  
In the current study, the results suggest that the receptor GPR55 had a pronociceptive role in neuropathic pain since CID16020046, a GPR55 antagonist, reduced tactile allodynia in L5-L6 spinal nerve ligation-induced neuropathic pain, and O-1602, a GPR55 agonist, prevented the antiallodynic effect induced by CID16020046. In this regard, O-1602 is considered an atypical cannabinoid that does not bind with high affinity to either CB1 or CB2 cannabinoid receptors [10]. Moreover, this drug has been postulated as a biased agonist of GPR18 receptors [20], but recent evidence with a selective agonist suggests that GPR18 activation induces anti-inflammatory and anti-nociceptive activities more than nociception [21]. On the other hand, CID16020046 is known as a selective GPR55 antagonist [22]. Thus, these effects seem to be mediated by GPR55 receptors instead of other receptors. To discount the participation of systemic effects or motor disturbances induced by spinal administration of CID16020046 or O-1602, the plasmatic glucose levels and motor coordination were evaluated with the highest doses tested of both drugs. Neither CID16020046 nor O-1602 at 300 \(\upmu\)g modified the plasmatic glucose levels or motor performance of the animals suggesting that the observed changes in the nociceptive behaviour were specific and local to the site of administration. The present results are consistent with previous reports that suggest that  
Figure 5: Western blotting analysis of GPR55 **(A–C)** and GPR119 **(D–F)** protein expression in ipsilateral lumbar spinal cord, L5-L6 dorsal root ganglia (DRG) and sciatic nerve of sham and L5-L6 spinal nerve ligation-induced neuropathic rats. Data were standardized in contrast to \(\upbeta\)-actin and they represent the mean \(\pm\) SEM of three independent experiments per group, where each experiment incorporated the tissue mixture of three rats. * Significantly different from sham group by one-way analysis of variance, followed by post hoc [PERSON]’s test with a \(p<0.05\). Abbreviations: SNL = spinal nerve ligation. GPR55 knockout mice have less tumour-induced mechanical hypersensitivity than control littermates [9], and failed to develop mechanical hyperalgesia in the partial nerve ligation model [14]. In contrast, one study concluded that there were no differences between GPR55 knockout mice and wild type mice in paclitaxel- or partial sciatic nerve injury-induced neuropathic pain [16]. This discrepancy could be related to the methodological tools used because the nociceptive role of GPR55 was described by a pharmacological approach [this study] and knockout mice generated by deleting GPR55 transmembrane domains [9; 14], whereas the lack of effect was found in knockout mice produced by deleting exon 2 [16]. In this regard, it is well known that genetic animal models often activate compensatory mechanisms that recruit the expression of other genes to mitigate the consequences of the deletion of the gene studied. Moreover, the difference in the result might also be attributed to the animal handling, rodent characteristics (species, sex, age and body weight) and pain models used in the studies. Consistent with our results, a recent study found that GPR55 receptors localised in the periaqueductal gray (PAG) participate in the maintenance of sciatic-nerve-injury-induced neuropathic pain in rats. This effect seems to implicate the activation of descending facilitation pathways involving the rostral ventromedial medulla toward the spinal cord [15]. In a similar way, another study showed that the microinjection of lysophosphatidylinositol (LPI) in the PAG reduced the paw withdrawal latency in a phasic pain model, an effect prevented by ML-193 [11]. The results suggest that the nociceptive role of the GPR55 receptor at PAG level is due to its activation increasing intracellular calcium levels via P/Q-type calcium channels and inositol 1,4,5-trisphosphate (IP3) receptors, and inducing the depolarization of PAG neurons stimulating descending facilitation pathways.