TABLE 6

Preclinical examinations of the glutamate system on the opioid withdrawal syndrome

Only results pertaining to effects of non-opioid drugs on opioid withdrawal symptoms are presented.

ReferenceDrugs Evaluated for Opioid Withdrawal Outcomes (Doses and Route)SpeciesSample SizeWithdrawal MethodDependence MethodWithdrawal Signs AssessedSummary of Withdrawal-Specified Results
Fundytus and Coderre (1994)MK-801, GYKI 52466, (S)-4C-PG, and L-AP3 (same dose schedule: 1.6, 8, and 40 nmol). Administered intracerebroventricularly.Rat4–10Precipitated, naloxone (1 mg/kg, s.c.), on day 7Morphine (36.65 µmol/day) administrated subcutaneously via pumpJumping, teeth chattering, wet dog shakes, and writingMK-801 (NMDA antagonist). (S)-4C-PG (metabotropic receptor antagonist), and L-AP3 (metabotropic receptor antagonist) dose dependently reduced teeth chattering and writing, as well as time spent in withdrawal. GYKI 52466 (AMPA/kainate receptor antagonist had no effect.
Fundytus and Coderre (1997)(1S,3R)-ACPD, DHPG, and L-AP4 (same dose scheduled: 0.12, 0.6, and 3 nmol), DCG-IV (4.8 or 24 pmol). Administrated intracerebroventricularly.Rat11–18Precipitated, naloxone (1 mg/kg, s.c.), on day 7Morphine (36.65 μmol/day) administrated subcutaneously via pumpDiarrhea, eye twitch, salivation, teeth chattering, and writing(1S,3R)-ACPD (mGlu nonspecific) decreased eye twitch severity and time spent in withdrawal. DCG-IV (mG1u2/3 antagonist) decreased diarrhea, eye twitch, salivation, and time spent in withdrawal. L-AP4 (mGlu4 antagonist) increased eye twitch. DHPG (mGlu1/5 antagonist) had no significant effect.
Fundytus et al. (1997)MCPG, MCCG, and MAP4 (same dose schedule: 1.6, 8, and 40 nmol/day). Administrated intracerebroventricularly.Rat17–20Precipitated, naloxone (1 mg/kg, s.c.), on day 7Morphine (75 mg) subcutaneous implant for 3 daysChewing, diarrhea, lacrimation, penile grooming, ptosis, salivation, stretching, teeth chattering, vocalization on touch, wet dogs shakes, and total withdrawal scoreMCPG (mGlu nonselective antagonist) decreased jumps, vocalization, wet dog shakes, and time spent in withdrawal. MCCG (mGlu2/3 antagonist) decreased jumping, wet dog shakes, and time spent in withdrawal. MAP4 (mGlu4,6,7,8 antagonist) decreased time spent in withdrawal.
Kosten et al. (1995)Felbamate (100 and 300 mg/kg), D-cycloserine (3 and 10 mg/kg), ± HA-966 (3, 10 mg/kg), Administered intraperitoneally.Rat6Precipitated, naloxone (10 mg/kg, s.c.) on day 4Morphine (75 mg) subcutaneous implant for 3 daysChewing, diarrhea, lacrimation, penile grooming, ptosis, salivation, stretching, teeth chattering, vocalization on touch, wet dog shakes, and total withdrawal scoreFelbamate (glycine antagonist) decreased frequency of chewing, penile grooming, teeth chatterin, and severity of salivation in a linear manner across doses. D-cycloserine (glycine agonist) decreased withdrawal severity at both doses but not in a linear way. ± HA-966 (partial glycine agonist) had no effect.
Kotlinkska and Bochenski (2007)MTEP (23 and 10 mg/kg), EMQMCM (5 and 20 mg/kg) Administered intraperitoneally.Mouse8–10Precipitated, naloxone (4 mp kg, i.p.) on day 3Morphine sensitization procedure for 13 days (10 mg/kg, i.p., every 3 days) followed by morphine (37.5 mg) subcutaneous implant for 3 daysJumpingMTEP (mGlu5 antagonist) 10 mg decreased jumping. EMQMCM (mGlu1 antagonist) had no effect.
Leal et al. (2003)Ibogaine (40 and 80 mg/kg), MK-801 (0.15, and 0.3 mg/kg), Ibogaine (40 mg/kg) + MK-801 (0.15 mg/kg). Administered intraperitoneally.Mouse10–13Precipitated, nalaxone (5 mg/kg, i.p.) on day 4Escalating morphine doses up to 225 mg/kg, i.p., by day 3JumpingAll doses of ibogaine and MK-801 (NMDA antagonist) decreased jumping. Ibogaine (40 mg/kg) and MK-801 (0.15 mg/kg) coadministration decreased jumping at the level observed for the high dose of each drug independently.
Medrano et al. (2015)Ceftriaxone (100 and 200 mg/kg), Topiramate (20 and 40 mg/kg). Administered intraperitoneally.Rat8–10Precipitated, naltrexone (10 mg/kg, i.p.) on day 4Morphine (200 mg/kg) subcutaneous implant for 3 daysAbnormal posture, body weight, diarrhea, exploring, ear blanching, eye twitching, jumping, lacrimation, mastication, penile erection, ejaculation, piloerection, ptosis, rhinorrhea, teeth chattering, vocalization on touch, and wet dog shakesCeftriaxone (glutamate transporter inhibitor) (200 mg/kg) decreased jumping, mastication, teeth chattering, and total withdrawal. Topiramate (glutamate release inhibitor) (40 mg/kg) reduced exploring, jumping, mastication, wet dog shakes, and total withdrawal score.
Pałucha-Poniewiera et al. (2009)ACPT-1 (2.5, 10, 30 mg/kg). Administered intraperitoneally.Mouse8–10Precipitated, naloxone (4 mg/kg, i.p.) on day 4Morphine (30 mg/kg, i.p.) for 3 days, with an additional dose on day 4Body tremor, body weight, jumping, paw shake, and wet dog shakesACPT-1 (mGlu2/3 agonist) decreased body tremor (all doses), body weight (10 and 30 mg), jumping (10 mg), paw shakes (10 and 30 mg), and wet dog shakes (all doses).
Rasmussen et al. (1996)LY293558 (0.1, 10, and 30 mg/kg). Administered intraperitoneally.Rat10–12Precipitated, naltrexone (10 mg/kg, s.c.) on day 4Morphine (150 mg) subcutaneous implant for 2 daysBody weight, chewing, diarrhea, digging, erections, irritability, jumping, lacrimation, ptosis, salivation, stereotyped head movements, teeth chattering, tremor, wet dog shakes, writhing, and total withdrawal scoreLY293558 (AMPA antagonist) dose dependently decreased total withdrawal score; specific dose-dependent decreases in chewing, diarrhea, lacrimation, ptosis, salivation, stretching head movements, wet dog shakes, and writhing.
Rasmussen et al. (2005)MPEP (1, 3, and 10 mg/kg), MTEP (1, 3, and 10 mg/kg). Administered intraperitoneally.Rat6–16Precipitated, naltrexone (10 mg/kg, s.c.) on day 3Morphine (75 mg) subcutaneous implant for 2 daysBody weight, chewing, diarrhea, digging, erection, irritability, jumping, lacrimation, ptosis, salivation, teeth chattering, wet dog shakes, writhing, and total withdrawal scoreMPEP (mGlu5 antagonist) reduced total withdrawal score at all doses tested and decreased body weight, chewing, digging, erection (1 mg/kg only), jumping, and teeth chattering (3 mg/kg only). MTEP (mGlu5 antagonist) 3 and 10 mg/kg reduced total withdrawal score and body weight, chewing, digging, erection (1 and 3 mg/kg only), and writhing.
Sekiya et al. (2004)DL-TBOA (1, 3, 10 nmol). Administered intracerebroventricularly.Rat6–7Precipitated, naloxone (0.1 mg/kg, i.p.) on day 5Morphine (150 mg) subcutaneous impart for 5 daysBackward walking, body weight, ejaculation, head shaking, jumping, paw shaking, stretching, teeth chattering, wet dog shakesDL-TBOA (glutmate uptake inhibitor) dose dependently increased ejaculation, rhinorrhea, salivation, teeth chattering, and wet dog shakes.
Tanganelli et al. (1991)MK-801 (0.1, 0.3, and 1 mg/kg), glutamatic acid dyethylester (100–500 mg/kg), pyroglutamic acid (500–1000 mg/kg). Administered intraperitoneally.Mouse15–20Precipitated, naloxone (3 mg/kg, s.c.) on day 2Morphine (75 mg) subcutaneous implant for 2 daysHyperactivity and jumpingMK-801 (NMDA antagonist) 0.3 and 1 mg/kg decreased jumping. Glutamatic acid dyethylester had no effect. Pyroglutamic acid (non-NMDA antagonist) 1000 mg/kg decreased jumping.
Tokuyama et al. (1996)MK-801 (0.1 mg/kg). Administered intraperitoneally.Rat10–14Precipitated, naloxone (48 nmol/5 µl, LC) or glutamate (1 and 10 nmol/5 µl, LC) 2 hours after last opioid infusionMorphine (26 nmol/µl per hour) or butorphanol (26 nmol/µl per hour) intracerebroventricular osmotic minipump infusions for 3 daysBody weight, escape behavior, locomotion, penis licking, ptosis, rearing, salivation, scratching, teeth chattering, and wet dog shakesGlutamate increased all withdrawal signs at both doses. MK-801 (NMDA antagonist) decreased all signs of withdrawal that were precipitated by either glutamate or naloxone.
Tokuyama et al. (1998)H-7 (1 and 10 nmol/µl per hour) intracerebroventricular osmotic minipump infusions.Rat7Precipitated, naloxone (24 and 48 nmol/5 µl, i.c.v.) or glutamate (1 and 10 nmol/5 µl, LC) 2 hours after opioid infusionMorphine (26 nmol/µl per hour) or butorphanol (26 nmol/µl per hour) intracerebroventricular osmotic minipump infusion for 3 daysBody weight, escape behavior, locomotion, penile licking, ptosis, rearing, salivation, stretching, teeth, chattering, and wet dog shakesGlutamate increased all signs except weight loss and salivation. H-7 (cAMP inhibitor) dose dependently decreased escape behavior, locomotion, penis licking, ptosis, rearing, salivation, streching, and teeth chattering. Outcomes are dependent on dependence and withdrawal method used.
Vandergriff and Rasmussen (1999)LY354740 (3, 10, and 30 mg/kg), LY317207 (30 mg/kg). Administered subcutaneously.Rat8Precipitated, naltrexone (10 mg/kg, s.c.) on day 3Morphine (300 g) subcutaneous implant for 2 daysBody weight, chewing, diarrhea, digging, erections, irritability, jumping, lacrimation, ptosis, salivation, stereotyped head movements, teeth chattering, wet dog shakes, writhing, and total withdrawal scoreLY354740 (mG1u2/3 agonist) dose dependently decreased total withdrawal score, chewing, diarrhea, digging, and salivation. Wet dog shakes and ptosis significantly decreased at 30 mg/kg only. LY317207 (inactive LY354740 enantiomer) had no effect.
Watanabe et al. (2002)CNQX (10 and 30 nmol), MK-801 (10 and 30 nmol), D-CPPene (0.001, 0.1, and 0.1 nmol) infusion to central nucleus of the amygdalaRat5–9Precipitated, naloxone (0.3 mg/kg, i.p.) on day 4Morphine (75 mg) subcutaneous implant for 2 daysBackward walking, body weight, diarrhea, head shakes, jumping, lacrimation, paw shakes, ptosis, rearing, rhinorrhea, salivation, stretching, teeth chattering, and wet dog shakesCNQX (AMPA/kainate antagonist) decreased backward walk, body weight loss, diarrhea, head shakes, paw shakes, ptosis, rhinorrhea, teeth chattering, and wet dog shakes. MK-801 (NMDA antagonist) and D-CPPene (NMDA antagonist) had no effect.
  • CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; LC, locus coeruleus; NR, not reported.