The γ₂-MSH peptide mediates a central analgesic effect via a GABA-ergic mechanism that is independent from activation of melanocortin receptors

Using the latency for tail-flick after thermal stimulation we have assessed the effects of α-, γ₁- and γ₂-MSH on nociceptive threshold in the mice. Intracisternal injections of γ₂-MSH induced a distinct analgesia, while γ₁-MSH in the same doses gave only a minor analgesia. Intracisternal α-MSH instead gave a short-term hyperalgesia. The effect of γ₂-MSH was not blocked by any of the MC₄/MC₃ receptor antagonist HS014, naloxone or by the prior intracisternal administrations of γ₁-MSH. However, the γ₂-MSH analgesic response was completely attenuated by treating animals with the GABA_A antagonist bicuculline. The γ₂-MSH analgesic effect was moreover additive to the analgesia afforded by muscimol and ethanol, but not to that afforded by diazepam. In addition both γ₁- and γ₂-MSH induced moderate catalepsy, but could at the same time attenuate haloperidol induced catalepsia. We conclude that γ₂-MSH mediates a central analgesic effect via GABA-receptor dependent pathway that is distinct from melanocortic- and opioid-receptors. Moreover, the mechanism for γ₂-MSH's analgesic effect appears to be distinct from that causing moderate catalepsia by γ-MSH's.