Location, Location, Location: The Effect of Lorcaserin via Different Routes of Administration on Acute Oxycodone Analgesia

Abstract

Pain is an unpleasant, subjective experience that serves as an important defense mechanism to noxious stimuli. There are several classes of analgesic drugs prescribed for the treatment of pain, with the most well‐known being opioids. Opioids are almost exclusively indicated for the treatment of moderate to severe pain but with their repeated use, there is a development of tolerance and dependence. With that known, there has been great interest to develop new analgesics or drug combinations that may reduce the incidence of side‐effects and facilitate the analgesic effects. Lorcaserin is a 5‐HT2C agonist that was originally indicated as a treatment for obesity but hypothesized as a potential treatment for drug dependence. Several preclinical studies have shown that lorcaserin reduced the self‐administration of several classes of drugs of abuse, including opiates. This observation prompted us to investigate whether lorcaserin would alter the basic pharmacology of opioids. To test this, we used a preclinical model (tail immersion test) that utilizes an acute, noxious thermal stimulus and is a heavily validated method for testing the antinociceptive properties of opiates. In the first round of studies we investigated the effect of subcutaneous lorcaserin pretreatment on the acute antinociceptive effect of oral oxycodone. All doses of lorcaserin tested produced a reversed dose‐response shift in the oxycodone curve (ED50 = 6.11mg/kg) to the left, with significant ED50 shifts occurring at 0.25mg/kg (ED50 =1.3mg/kg), 0.5mg/kg (ED50 = 1.21mg/kg), 1mg/kg (ED50= 2.08mg/kg), and 2mg/kg of lorcaserin (ED50=3.77mg/kg). It is important to note that none of the subcutaneous doses of lorcaserin tested had an antinociceptive effect on their own. Next, we administered lorcaserin via different routes of administration and found that its effects vary depending upon route of administration. Lorcaserin, administered via the intracerebroventricular route at 32, 64 or 128ug did not demonstrate antinociceptive activity but intrathecal lorcaserin (8, 16, 32, 64, 128ug) demonstrated a full dose‐responsive effect, with an ED50 of 54ug. Interestingly, we observed that ICV lorcaserin attenuated oral oxycodone's antinociceptive effects by 40%. Our results indicate that there are significant regional differences in the effect of lorcaserin and the 5‐HT2c receptor plays a differential role depending on the region of the central nervous system in the antinociception elicited by oxycodone. Further studies will investigate the role of potential off‐target effects of lorcaserin that may be mediated through the 5‐HT2A receptor.Support or Funding InformationFunding provided by USPHS grant number DA036975.