Background: Tramadol has a high potential for misuse resulting in cognitive impairment.
Zingiber officinale, however, possesses neuroprotective qualities. Objective: Microscopically
assessed hippocampal CA1 and CA3 following Z. officinale and tramadol treatment.
Materials and Methods: Two milliliters/kilogram of distilled water was given to Group 1,
Groups 2–5 were administered 50 mg/kg of tramadol while Group 3 was also administered 12.5 mg/
kg of naltrexone, and Groups 4 and 5 were also administered 500, and 1000 mg/kg ethanol extract of
Z. officinale (EEZO), respectively, orally for 21 days. The rats were euthanized and their brains were
collected, fixed in 10% formal saline, and processed routinely using crystal fast violet (CFV) stain for
the demonstration of Nissl substance, glial fibrillary acidic protein (GFAP) for the demonstration of
astrocytes, and Hematoxylin and Eosin for general histoarchitecture and estimation of cell number and
volume using physical dissector and Cavalieri estimator, respectively. Results: CFV stain revealed
alterations in regions of CA1 and CA3 of the hippocampus presenting as indistinct staining intensity
and peripheral Nissl substance accumulation in the tramadol‑treated group. GFAP revealed numerous
reactive astrocyte processes. The area of reactive astrocytes remarkably increased (P < 0.05) and
the intensity of the Nissl substance remarkably reduced in the tramadol-exposed group. When
compared to the control, the tramadol-exposed group’s hippocampal volume considerably (P < 0.05)
decreased (coefficient of error [CE] =0.050). The tramadol treatment group (CE = 0.090) relative to
the control group (CE = 0.060) showed a striking decrease (P < 0.05) in the number of pyramidal
cells in the CA3 region. The tramadol treatment group (CE = 0.090) compared to the control
group (CE = 0.060) showed a striking decrease (P < 0.05) in the number of pyramidal cells in the
CA3 region. Tramadol toxicity was attenuated in the groups treated with EEZO in a dose-dependent
manner. Conclusion: Z. officinale possesses a potential neuroprotective effect against tramadol‑induced
neurotoxicity.