Preclinical examinations of the serotonin system on the opioid withdrawal syndrome
Only results pertaining to effects of non-opioid drugs on opioid withdrawal symptoms are presented.
| Reference | Drugs Evaluated for Opioid Withdrawal Outcomes (Dose and Route) | Species | Sample Size | Withdrawal Method | Dependence Method | Withdrawal Signs Assessed | Summary of Withdrawal-Specific Results |
|---|---|---|---|---|---|---|---|
| Cervo et al. (1981) | d-fenfluramine (5 mg/kg), cyproheptadine HLC (10 mg/kg), clonidine (0.1 mg/kg), phentolamine methane sulphonate (5 mg/kg), piperoxane HCL (5, 10 mg/kg), phenoxybenzamine HCL (20 mg/kg), prazosin HCL (10 mg/kg), propranolol (10 mg/kg), haloperidol (1 mg/kg), piribedil monometane sulphonate (60 mg/kg). Administered intraperitoneally. | Rat | ≥18 | Precipitated, naloxone (1 mg/kg, i.p.) on day 11 | Escalating morphine (route NR) doses up to 160 mg/kg by day 7 | Diarrhea, flat posture, jumping, ptosis, salivation, teeth chattering, vocalization on touch, and wet dog shakes | d-fenfluramine (SSRI) reduced jumping only. Clonidine (α2 agonist) reduced diarrhea and ptosis. Phenoxybenzamine (adrenergic antagonist) reduced diarrhea. The adrenergic antagonists piperoxane, phentolamine methane sulphonate, prazosin (α1), propranolol (β1), haloperidol, and peribedil monometane sulphonate (α2) had no effects. |
| el-Kadi and Sharif (1995) | Cyproheptadine (0.5, 1, 5, and 10 mg/kg), methysergide (0.1, 1, 3, and 6 mg/kg). Administered intraperitoneally. | Mouse | 8–10 | Precipitated, naloxone (1 mg/kg, i.p.) on day 7 | Escalating morphine doses up to 160 mg/kg, s.c., by day 6 | Body temperature, body weight, burrowing, jumping, and wet dog shakes | Cyproheptadine (5-HT2A,2C antagonist) increased jumping (0.5 and 1 mg/kg) and hypothermia (all doses) and decreased jumping (5 and 10 mg/kg), wet dog shakes (all doses), burrows (10 mg/kg), and body weight loss (5 and 10 mg/kg). Methysergide (5-HT2 antagonist and 5-HT1A agonist) decreased burrowing, jumping, and wet dog shakes (all doses), and body weight loss (1, 3, and 6 mg/kg) but increased hypothermia (1, 3, and 6 mg/kg). |
| Higgins et al. (1991) | Ondansetron (0.01, 0.1, and 1 mg/kg), MDL 7222 (1 and 3 mg/kg). Administered subcutaneously. | Rat | 6 | Precipitated, naloxone (0.5 mg/kg, s.c.) on days 3 and 4 | Morphine (75 mg) subcutaneous implant | Body temperature, paw shakes, mouth movements, salivation, startle, rhinorrhea, penile grooming, teeth chattering, weight loss, and wet dog shakes | Ondansetron (5-HT3 antagonist) attenuated body weight loss (0.1 and 1 mg/kg). MDL 7222 (5-HT3 antagonist) also attenuated body weight loss (3 mg/kg). |
| Pang et al. (2016) | Glemanserin (0.5 mg/kg). Administered intraperitoneally. | Mouse | 10 | Precipitated, naloxone (5 mg/kg, i.p.) on day 7 | Escalating morphine doses up to 100 mg/kg, s.c., by day 6 | Body grooming, burrowing, digging body, extended posture, face grooming, head shakes, jumping, paw licking, penile licking, rearing, scratching, and wet dog shakes | Glemanserin (5-HT2A antagonist) decreased jumping (0.5 mg/kg). |
| Pinelli et al. (1997) | Ondansetron (0, 1, 2, and 4 mg/kg). Administered intraperitoneally. | Rat | 8 | Precipitated, naloxone (30 mg/kg, i.p.) on day 4 | Escalating morphine doses up to 100 mg/kg, i.p., by day 4 | Body temperature, defecation, jumping, salivation, urine excretion, and wet dog shakes | Ondansetron (5-HT3 antagonist) reduced defecation (1, 2, and 4 mg/kg), body temperature (4 mg/kg), and jumping (2 and 4 mg/kg), but increased wet dog shakes (1, 2, and 4 mg/kg). |
| Romandini et al. (1984) | (+)-Fenfluramine (5 mg/kg); m-chlorophenylpiperazine (CPP; 2.5 mg/kg), Clonidine (0.5 mg/kg). Administered intraperitoneally. | Rat | ≥16 | Precipitated, naloxone (1 mg/kg, i.p.). Experiment 1 tested on Day 3; Experiment 2 on Day 5 | Experiment 1: Morphine (75 mg) subcutaneous implant; Experiment 2: Escalating morphine doses up to 40 mg/kg, i.p., by day 5 | Abnormal posture, diarrhea, jumping, ptosis, salivation, teeth chattering, vocalization on touch, wet dog shakes | (−)-fenfluramine (SSRI) and and m-CPP (5-HT agonist) decreased jumping. Clonidine (α2 agonist) reduced wet dog shakes and increased jumping. |
| Samanin et al. (1980) | Quipazine (5 mg/kg), m-CPP (2.5 mg/kg); clonidine (0.5 mg/kg), haloperidol (0.5 mg/kg), propranolol hydrochloride (10 mg/kg). Administered intraperitoneally. | Rat | NR | Precipitated, naloxone (1 mg/kg, i.p.) on day 11 | Escalating morphine doses up to 160 mg/kg, s.c., by day 7 | Diarrhea, dyspnea, flat posture, jumping, ptosis, teeth chattering, salivation, vocalization on touch, and wet dog shakes | m-CPP (5-HT2C agonist) decreased diarrhea and jumping. Quizapine (5-HT2A/3 agonist) decreased jumping. Clonidine (α2 agonist) decreased diarrhea and ptosis. Propranolol and haloperidol had no effect. |
| Shahidi and Hashemi-Firouzi (2014) | AS19 (3, 5, and 10 mg/kg); SB269970 (1, 3, and 10 mg/kg). Administered intraperitoneally. | Mouse | 8 | Precipitated, naloxone (3 mg/kg, s.c.) on day 5 | Escalating morphine doses up to 45 mg/kg, s.c., by day 5 | Body grooming, body weight, face grooming, head shakes, jumping, limb shakes, sniffing, standing, teeth chattering, and writhing | AS19 (5-HT7 agonist) decreased weight loss (all doses); jumping, head shaking, standing, and writhing (5 and 10 mg/kg); and teeth chattering and limb shaking (10 mg/kg). SB269970 (5-HT7A antagonist) increased teeth chattering (10 mg/kg) and limb shaking (1 mg/kg). |
| Wu et al. (2015) | Lorcaserin (0.5 mg/kg), clonidine (0.05 mg/kg). Administered intraperitoneally. | Mouse | 10 | Precipitated, naloxone (5 mg/kg, i.p.) on day 5 | Escalating diacetyl morphine doses up to 50 mg/kg, s.c., by day 5 | Body grooming, burrowing, digging body, extended posture, head shakes, jumping, paw licking, penile grooming, rearing, and wet dog shakes | Lorcaserin (5-HT2C agonist) decreased jumping and paw licking. Clonidine (α2 agonist) decreased jumping and paw licking. |
| Zhang et al. (2016) | Lorcaserin (0.5, 0.75, and 1.0 mg/kg), SB242084 (1.0 mg/kg), Clonidine (0.2 mg/kg). Administered intraperitoneally. | Mouse | 9 to 10 | Precipitated, naloxone (5 mg/kg, i.p.) on day 7 | Escalating morphine doses up to 100 mg/kg, s.c., by day 6 | Body grooming, burrowing, defecation, digging body, extended posture, face grooming, head shakes, jumping, paw licking, penile licking, piloerection, ptosis, rearing, scratching, urination, vocalization on touch, and wet dog shakes | Lorcaserin (5-HT2C agonist) decreased jumping, burrowing, body grooming, rearing, wet dog shakes, paw licking, penile licking, and scratching (all doses). Clonidine (α2 agonist) decreased jumping, burrowing, body grooming, rearing, wet dog shakes, head shakes, paw licking, penile licking, and scratching (0.2 mg/kg). SB242084 (5-HT2C antagonist; 0.2 mg/kg) pretreatment blocked lorcaserin (0.5 mg/kg) suppression of jumping. |
m-CPP, meta-chlorophenylpiperazine; SSRI, selective serotonin reuptake inhibitor; NR, not reported.