TABLE 5

Preclinical examination of the orexin/hypocretin 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 (Dose and Route)aSpeciesSample SizeWithdrawal MethodDependence MethodWithdrawal Signs AssessedSummary of Withdrawal-Specific Results
Ahmadi-Soleimani et al. (2014)SB-334867 (100 µM/0.2 µl). Direct administration to LPGi nucleus.Rat8–13Precipitated, naloxone (2 mg/kg, i.p.). Injection occurred following morphine escalation, specific time NREscalating mrophine (drinking water) increasing in concentrations up to 0.4 mg/ml and maintained for 15 daysChewing, defecation, digging, genital licking, grooming, rearing, sniffing, teeth chattering, and wet dog shakesSB-334867 decreased chewing, genital licking, grooming, rearing, and sniffing.
Azizi et al. (2010)SB-334867 (100 µM/0.2 µl). Direct administration to locus coereleus.Rat9Precipitated, naloxone (1 mg/kg, i.p.) 2 hours after morphine administration on day 10Morphine (10 mg/kg) delivered every 12 hours for 10 daysChewing, diarrhea, head tremor, jumping, rearing, scratching, sniffing, teeth chattering, ptosis, and wet dog shakesSB-334867 decreased chewing, diarrhea, head tremor, scratching, teeth chattering, and wet dog shakes.
Davoudi et al. (2016)SB-334867 (3 mM/0.2 µl). Bicuculline (15 µM/0.2 µl). Direct administration to locus coereleus.Rat7Precipitated, naloxone (3 mg/kg, s.c.) on day 8Escalating morphine doses up to 66 mg/kg, s.c., by day 7Defecation, head tremor, genital licking, rearing, scratching, sniffing, teeth chatttering, wet dog shake, and writhingSB-334867 decreased defecation, head tremor, gential licking, rearing, scratching, sniffing, wet dog shakes, and writhing. Bicuculline (GABA antagonist) had no effect by itself but when coadministered with SB-334867 reversed effects on head tremor, rearing, scratching, teeth chattering, wet dog shakes, and writhing.
Erami et al. (2012)SB-334867 (1 mM/5 µl). Administered intracerebroventricularly.Rat8Precipitated, nalozone (2 mg/kg, s.c.) on day 10Morphine (10 mg/kg, s.c.) delivered every 12 hours for 10 daysChewing, climbing, defecation, diarrhea, head tremor, jumping, rearing, scratching, sniffing, teeth chattering, and wet dog shakesSB-334867 decreased chewing, climbing, diarrhea, jumping, rearing, rhinorrhea, and teeth chattering.
Ghaemi-Jandabi et al. (2014)Orexin A (100 µM/200 nl); SB-334867 (100 µM/200 nl). Direct administration to locus coereleus.Rat6 to 7Precipiated, OXA (0.2 µl) injection to locus coereleus on day 10Morphine (10 mg/kg, s.c.) delivered every 12 hours for 9 daysChewing, head tremor, paw tremor, rearing, scratching, sniffing, teeth chattering, and wet dog shakesOXA increased chewing, head tremor, rearing, scratching, and wet dog shakes. SB-33847 decreased chewing, head tremor, paw tremor, scratching, sniffing, rearing, and teeth chattering.
Hooshmand et al. (2017)SB-334867 (3 mM/200 nl) + glutamate (100 nM/200 nl). Direct administration to locus coereleus.RatNRPrecipitated, glutamate (100 nM/200 nl) injection to locus coereleus on day 7Escalating morphine up to 66 mg/kg, s.c., by day 7Chewing, defecation, head tremor, paw tremor, rearing, scratching, sniffing, teeth chattering, wet dog shakes, and writhingGlutamate increased chewing, paw tremor rearing, scratching, sniffing, wet dog shakes, and writhing. SB-334867 pretreatment did not attenuate glutamate-precipitated withdrawal during the day (rest phase) but decreased chewing, head tremor, paw tremor, rearing, sniffing, scratching, teeth chattering, wet dog shakes, and writhing during the night (active phase).
Hooshmandi et al. (2017)SB-334867 (0.5 µg/0.5 µl). Direct administration to dorsal hippocampus.Rat12Precipitated, naloxone (1.5 mg/kg, i.p.) on day 10Morphine (10 mg/kg, s.c.) delivered every 12 hours for 9 days.Activity, chewing, diarrhea, head tremor, freezing, penile licking, ptosis, rearing, rubbing, scratching, sniffing, teeth chattering, wet dog shakes, and writhingSB-334867 decreased chewing, diarrhea, freezing, penile licking, ptosis, scratching, teeth chattering, wet dog shakes, and writhing.
Laorden et al. (2012)SB-334867 (20 mg/kg). Administered intraperitoneally.Rat4–8Precipitated, naloxone (1 mg/kg, s.c.) on day 6Morphine (150 mg) subcutaneous implant for 6 daysDiarrhea, jumping, mastication, paw tremor, piloerection, ptosis, sniffing, teeth chattering, tremor, wet dog shakes, and writhingSB-334867 decreased body tremor, diarrhea, mastication, piloerection, ptosis, sniffing, wet dog shakes, and writhing. Global withdrawal score also decreased.
Sharf et al. (2008)SB-334867 (0, 20 mg/kg). Direct administration to nucleus accumbens.Mouse9Precipitated, naloxone (1 mg/kg, s.c.) 2 hours after morphine administrationEscalating morphine doses up to 100 mg/kg, i.p., for 2.5 daysBackward walking, gnawing, head swoops, jumping, paw tremors, ptosis, tremors, and wet dog shakesSB-334867 decreased backward walking, ptosis, tremors, wet dog shakes, and global withdrawal score (sum of withdrawal symptoms).
  • LPGi, lateral paragigantocellularis; NR, not reported.

  • a All drugs were administered to specific brain regions, except where noted.