Background L-
acetylcarnitine, a drug marketed for the treatment of
chronic pain, causes
analgesia by epigenetically up-regulating type-2 metabotropic
glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that
analgesia could outlast the duration of L-
acetylcarnitine treatment in models of inflammatory and
neuropathic pain. Results A seven-day treatment with L-
acetylcarnitine (100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete
Freund adjuvant mouse model of chronic inflammatory
pain. L-
Acetylcarnitine-induced
analgesia persisted for at least 14 days after drug withdrawal. In contrast, the
analgesic effect of
pregabalin, amitryptiline,
ceftriaxone, and
N-acetylcysteine disappeared seven days after drug withdrawal. L-
acetylcarnitine treatment enhanced mGlu2/3 receptor
protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated
histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting
analgesic effect of L-
acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with
pregabalin, amitryptiline,
tramadol, or L-
acetylcarnitine produced a significant antiallodynic effect, with
pregabalin displaying the greatest efficacy. In mice treated with
pregabalin,
tramadol or L-
acetylcarnitine the
analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-
acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor
protein levels in the dorsal horns of the spinal cord. Conclusions Our findings suggest that L-
acetylcarnitine has the unique property to cause a long-lasting
analgesic effect that might reduce relapses in patients suffering from
chronic pain.