THE ROLE OF ANGIOTENSIN II RECEPTOR TYPE 1 AND PPARγ IN OPIOID ANALGESIC TOLERANCE

Introduction: Opioid analgesics are the mainstay in the management of moderate to severe pain, however their effectiveness is hampered by side effects such as analgesic tolerance. Recent studies indicate that AT1 receptor blockers (ARBs), particularly telmisartan, have shown antinociception in chronic pain and delayed morphine tolerance, yet telmisartan activates peroxisome proliferator-activated receptor gamma (PPARγ). Thus, further studies on AT1 blockage or PPARγ activation are needed. Aim: Exploring whether morphine analgesic tolerance is mediated by AT1 or PPARγ, telmisartan and losartan were assessed using in vivo and in vitro assays. Methods: Male Wistar rats (180-250 g) and NMRI mice (35-45 g) were used. The rat tail-flick assay was used to test the antinociceptive effects of subcutaneous morphine (31.08 µmol/kg), oral telmisartan (20 µmol/kg), or losartan (50 µmol/kg), either individually or in combination with morphine, acutely and at 4 and 10 days after treatment and at 60, 90, 150 and 210 min post-administration. Test compounds and combinations were also analyzed in the presence of 7.22 µmol/kg intraperitoneal GW9662, a PPARγ antagonist. The respective vehicles for the test compounds were tested. Post-antinociceptive measurement, animals were sacrificed, and their spinal cords were removed for histological analysis. For the purpose of colocalization study, naïve rats were used. In the in vitro assay, mouse vas deferens (MVD) was utilized. Briefly, the MVD was equilibrated under field electrical stimulation for 60 minuted, followed by three treatments with vehicle, 1000 nM morphine alone or in combination with losartan, and then received 500 nM morphine. Results: Morphine failed to show an antinociceptive effect by day 10 of treatment, as indicated by tail-flick latency, suggesting the development of antinociceptive tolerance. In contrast, morphine in combination with telmisartan or losartan showed GW9662-sensitive antinociception. On the other hand, telmisartan or losartan alone failed to show an effect after either acute or chronic administration. Morphine treatment increased dorsal horn spinal IBA1 expression, which was attenuated by ARBs. GW9662 reversed ARBs’ effect. Colocalization of AT1 and MOR on small to medium sized primary afferent neurons was observed, yet the double-positive cells were mostly CGRP positive. Compared to vehicle-treated MVD, the effect of 500 nM morphine significantly decreased in tissues exposed to repeated 1000 nM morphine treatment, indicating the development of morphine tolerance in the in vitro assay. Concomitant treatment of MVD with morphine and losartan restored the effect of 500 nM morphine. Conclusion: Simultaneous activation of MOR and inhibition of AT1 can delay the development of morphine tolerance in vivo and attenuate in vitro; however, this effect is also PPARγ dependent.