Quantitative opioid withdrawal signs in rats: effects exerted by clothiapine administration

Abstract

An opioid withdrawal syndrome, which causes alteration of several physiological signs, was induced in rats by repeated morphine administration and final naloxone injection. The aim of this study was prevention of the altered physiological profiles by utilising clothiapine, which is capable of affecting fecal and urinary excretion, rectal temperature, pain threshold levels and salivatory behaviour. Morphine was administered in three daily intraperitoneal (ip) injections for 4 days at doses of 9, 16 and 25 mg/kg (d 1), 25, 25 and 50 mg/kg (d 2), 50, 50 and 50 mg/kg (d 3) and 50, 50 and 100 mg/kg (d 4). Naloxone was injected (30 mg/kg) ip 180 min after the last morphine injection. Clothiapine was administered orally 0.7, 2 and 6 mg/kg 2 hours before the naloxone administration. Signs such as fecal and urine excretion, rectal temperature and latency times to thermal stimulus salivation, jumping and wet dog shakes were affected in different ways by morphine, naloxone, clothiapine and combination of them. Notably the administration of clothiapine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, such as altered excretion of feces, temperature values, salivation, jumping and wet dog shakes behaviour, and elevated the nociceptive threshold values. The effects exhibited by clothiapine administration may be explained through its antimuscarinic, antiadrenergic and antidopaminergic activities interfering with the mechanisms involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of the acute phase of opioid withdrawal in heroin addicts.

Biological sex influences sleep phenotype in mice experiencing spontaneous opioid withdrawal

“…In our study, we utilized a 5‐day treatment paradigm to induce opioid withdrawal, whereas OUD is normally associated with longer term opioid abuse, lasting years or decades (He et al, 2020). In the preclinical literature, animals are usually treated with injection protocols typically ranging from 4 to 14 days (Gallego et al, 2010; McGregor et al, 2022; Pinelli et al, 1997). As such, physiological changes occurring as the result of longer‐term opioid use may not be fully recapitulated in these animal models.…”

Subdiaphragmatic vagal afferent innervation in activation of an opioidergic antinociceptive system in response to colorectal distension in rats

“…This dose of naloxone was chosen on the basis of experiments in which abdominal musculature electromyogram activity was measured in response to colorectal distension after administration of different doses of naloxone (0.1-100 mg kg )1 i.p., unpublished observation) and previous publications on the effect of naloxone in rodents. 14,15 Experiments were performed in sham vagotomized rats (n ¼ 6), subdiaphragmatically vagotomized rats (n ¼ 7), perineural vehicle-(n ¼ 5) or capsaicin-treated rats (n ¼ 6). On separate days, rats were pretreated with naloxone 10 min before experiments.…”

Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement

“…This dose was selected based on data indicating that 10 mg/kg was adequate to achieve conditioned place preference within this time period (Lu et al, 2005;Raghavendra et al, 2004), and that a single dose was able to elicit conditioned place avoidance after a naloxone challenge (Araki et al, 2004). Morphine administration at this dose for 5 days also produced analgesic tolerance (Beaudry et al, 2009), and after only 4 days, produced withdrawal behaviors including increased defecation, urination, salivation, jumping, and wet dog shakes (Pinelli et al, 1997). Finally, this dosing schedule activated glial cells and enhanced proinflammatory cytokine expression in the spinal cord that has been implicated in morphine tolerance and withdrawal-induced hyperalgesia (Raghavendra et al, 2004).…”