Melatonin is a remarkable molecule with diverse physiological functions. Some of its effects are mediated by receptors while other, like cytoprotection, seem to depend on direct and indirect scavenging of
free radicals not involving receptors. Among
melatonin's many effects, its antinociceptive actions have attracted attention. When given orally, intraperitoneally, locally, intrathecally or through intracerebroventricular routes,
melatonin exerts antinociceptive and antiallodynic actions in a variety of animal models. These effects have been demonstrated in animal models of
acute pain like the tail-flick test,
formalin test or
endotoxin-induced
hyperalgesia as well as in models of
neuropathic pain like nerve
ligation.
Glutamate,
gamma-aminobutyric acid, and particularly,
opioid neurotransmission have been demonstrated to be involved in
melatonin's
analgesia. Results using
melatonin receptor antagonists support the participation of
melatonin receptors in
melatonin's
analgesia. However, discrepancies between the affinity of the receptors and the very high doses of
melatonin needed to cause effects in vivo raise doubts about the uniqueness of that physiopathological interpretation. Indeed,
melatonin could play a role in
pain through several alternative mechanisms including
free radicals scavenging or
nitric oxide synthase inhibition. The use of
melatonin analogs like the MT(1)/MT(2) agonist
ramelteon, which lacks
free radical scavenging activity, could be useful to unravel the mechanism of action of
melatonin in
analgesia.
Melatonin has a promising role as an
analgesic drug that could be used for alleviating
pain associated with
cancer,
headache or
surgical procedures.