Acute oxycodone induces the pro-emetic pica response in rats

Abstract

Oxycodone, a semisynthetic opioid analgesic, is frequently prescribed for the management of pain. Side effects of nausea and emesis affect patient compliance and limit its therapeutic use. The present study established that an antinociceptive dose of oxycodone (15 mg/kg; oral) induces the pica response. We found sex differences in the temporal course of pica, with females having a longer duration. Opioid receptors mediated the pica response, as 1.0 mg/kg naloxone transiently attenuated and 2.0 mg/kg naloxone blocked pica. A κ-selective antagonist failed to block the response, suggesting mediation by μ opioid receptor. For further validation, we used the well established kaolin intake model to assess pica with the chemotherapeutic drug cisplatin as a positive control. Oxycodone and cisplatin significantly increased kaolin intake 4- to 7-fold, and the wet weight of stomach was elevated 2- to 3-fold. To examine the underlying neural circuitry, we investigated c-fos activation in the area postrema and nucleus of solitary tract (NTS). Oxycodone treatment significantly increased the number of c-fos-positive neurons in the area postrema and NTS compared with water controls. As expected, cisplatin also increased the number of c-fos-positive cells in these regions. In the area postrema, the oxycodone effect was greater than cisplatin, especially at 2 h. These results indicate that an antinociceptive dose of oxycodone is associated with the expression of pica, a pro-emetic response.

Fig. 1.

a, male and female rats (n = 6 per group) have increased intake of cage bedding after oral administration of oxycodone (15 mg/kg). The graph depicts the percentage of responses that were positive for bedding intake collapsed across each hour. This intake is sustained for 3 to 4 h. No bedding intake was found before drug treatment or after vehicle administration. Overall, females displayed a greater pica response than males (*, p < 0.05 versus baseline within each sex; χ² analysis). b, naloxone blocked or attenuated the pica response to oxycodone in female rats. The 2 mg/kg dose decreased the bedding intake across the 3-h session, whereas the 1 mg/kg dose transiently attenuated the response at 2 h (*, p < 0.05 versus oxycodone; Tukey's post hoc test). n = 6 per group. c, the selective κ antagonist Nor-BNI did not alter the oxycodone-induced pica response in female rats. n = 4 for saline + oxycodone (Saline + Oxy), and n = 6 for the Nor-BNI + oxycodone (NX + Oxy) groups.

Fig. 2.

a, oxycodone-induced pica manifests as increased kaolin intake in female rats (n = 4–6). Kaolin intake was monitored over two 3-h sessions across 2 days. Data are represented as kaolin intake in grams. Cisplatin also increased kaolin intake compared with controls. b, cisplatin and oxycodone significantly increased the wet weight (in grams) of the stomach compared with the control group in these female rats. *, p < 0.05 compared with control; post hoc Tukey's test. n = 5 to 7 per group.

Fig. 3.

Immunohistochemical staining for oxycodone-induced c-fos activation in emetic circuitry after oxycodone or cisplatin administration. The area postrema (top) and the NTS (bottom) are shown. Compared with control, increased c-fos-positive cells were observed in cisplatin- and oxycodone-treated rats 1 and 2 h after treatment. Magnification, 10×.

Fig. 4.

Quantification of c-fos in emesis-related circuitry after cisplatin or oxycodone (OXY) treatment. Controls were collapsed across saline- and water-treated groups. Depicted are the mean ± S.E.M. for the number of c-fos-positive cells summed across the anterior, medial, and posterior regions. a, in the area postrema, cisplatin and both oxycodone time points increased c-fos expression, with the greatest effect 2 h after treatment. b, similar effects were found in the NTS, where oxycodone and cisplatin increased the number of c-fos-positive cells. *, p < 0.05 versus control; ^, p < 0.05 versus cisplatin; #, p < 0.05 versus 1-h oxycodone. n = 10 for controls; n = 4 for cisplatin; n = 5 to 6 for oxycodone treated.