Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice.

Abstract

This study evaluated the hypothesis that a paclitaxel treatment regimen sufficient to produce mechanical allodynia would alter sensitivities of male and female mice to the conditioned rewarding and reinforcing effects of morphine. Saline or paclitaxel were administered on days 1, 3, 5, and 7 in male and female C57Bl/6 mice to induce morphine-reversible mechanical allodynia as measured by the Von Frey filament test. Paclitaxel treatment did not change sensitivity to morphine conditioned place preference (CPP) relative to saline treatment in either male or female mice. Morphine produced peak self-administration under a fixed ratio-1 schedule of reinforcement for 0.03 mg/kg morphine per infusion in female mice and 0.1 mg/kg morphine per infusion in male mice. During the progressive ratio experiments, saline treatment in male mice decreased the number of morphine infusions for 12 days whereas the paclitaxel-treated male mice maintained responding for morphine similar to baseline levels during the same time period. However, paclitaxel did not have an overall effect on the reinforcing efficacy of morphine assessed over a limited dose range during the course of the repeated self-administration. These results suggest that the reward-related behavioral effects of morphine are overall not robustly altered by the presence of paclitaxel treatment under the current dosing regimen, with the exception of maintaining a small yet significant higher baseline than saline treatment during the development of allodynia in male mice.

Inhibitory transmission in the bed nucleus of the stria terminalis in male and female mice following morphine withdrawal

“…Although sex differences in the analgesic potency of opioids have been examined previously, both male and female mice develop conditioned place preference to the same dose (10 mg/kg) of morphine, which suggests that the rewarding and analgesic effects of opioids may be mediated through distinct circuitries. Few studies, however, have investigated withdrawal characteristics in male and female rodents .…”

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

“…To attempt to model the physiological and behavioral changes in OUD, many researchers use relatively high doses of morphine and/or escalating doses to induce both acute and chronic physical dependence (Goeldner et al, ; Kest, Palmese, Hopkins, Adler, & Juni, ; Valentinova et al, ). It has been observed, however, that acute dependence can be induced with a rewarding, albeit lower dose of morphine (10 mg/kg) and precipitated withdrawal with relatively low doses of the opioid receptor antagonist naloxone (1 mg/kg, Le Merrer, Faget, Matifas, & Kieffer, ; Neelakantan, Ward, & Walker, ; Schulteis et al, , ). Investigating physiological and behavioral changes to lower doses of opioids may be clinically relevant in the current opioid crisis, as 80% of new heroin users report previous prescription opioid use (Cicero & Kuehn, 2014).…”

“…Sex differences in analgesic responses to opioids have been observed in both humans and mice, wherein females are less sensitive to the pain‐relieving properties of these drugs (Kest, Sarton, & Dahan, ). However, females also show equal or enhanced responses to the rewarding properties of opioids (Le Merrer et al, ; Neelakantan et al, ; Pleil & Skelly, ), suggesting a dissociation between these two interoceptive states in response to opioids. Because of the association between locomotor sensitization and compulsive drug seeking and taking (Robinson & Berridge, ; Vezina, ), the lasting effects we observe here in protracted withdrawal may be highly significant for potential propensity to relapse.…”

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

“…To attempt to model the physiological and behavioral changes in OUD, many researchers use relatively high doses of morphine, and/or escalating doses to induce both acute and chronic physical dependence (Kest et al, 2001;Goeldner et al, 2011;Valentinova et al, 2019). It has been observed, however, that acute dependence can be induced with a rewarding, albeit lower dose of morphine (10 mg/kg) and precipitated withdrawal with relatively low doses of the opioid receptor antagonist naloxone (1 mg/kg) (Schulteis et al, 1998(Schulteis et al, , 1999Le Merrer et al, 2012;Neelakantan et al, 2016). Investigating physiological and behavioral changes to lower doses of opioids may be clinically relevant in the current opioid crisis, as 80% of new heroin users report previous prescription opioid use (Cicero & Kuehn, 2014).…”

“…Sex differences in analgesic responses to opioids have been observed in both humans and mice, wherein females are less sensitive to the pain-relieving properties of these drugs (Kest et al, 2000). However, females also show equal or enhanced responses to the rewarding properties of opioids (Le Merrer et al, 2012;Neelakantan et al, 2016;Pleil & Skelly, 2018), suggesting a dissociation between these two interoceptive states in response to opioids. Because of the association between locomotor sensitization and compulsive drug seeking and taking (Robinson & Berridge, 2003;Vezina, 2004), the lasting effects we observe here in protracted withdrawal may be highly significant for potential propensity to relapse.…”