Systemic administration of
morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 microg/kg). We have examined in vivo whether
morphine, at an extremely low dose, induces acute central hypernociception following activation of the
opioid receptor-mediated PLC/PKC
inositol-
lipid signaling pathway. The PLC inhibitor
U73122 and the PKC blocker,
calphostin C, dose dependently prevented the thermal hypernociception induced by
morphine. This effect was also prevented by pretreatment with aODN against PLCbeta3 at 2 nmol/mouse and PKCgamma at 2-3 nmol/mouse. Low dose
morphine hyperalgesia was dose dependently reversed by selective
NMDA antagonist
MK801 and
ketamine. This study demonstrates the presence of a nociceptive PLCbeta3/PKCgamma/
NMDA pathway stimulated by low concentrations of
morphine, through muOR1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in
morphine analgesia. When mice were treated with a
morphine analgesic dose (7 mg/kg), the downregulation of PLCbeta3 or PKCgamma at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in
analgesic response. Experimental and clinical studies suggest that
opioid may activate pronociceptive systems, leading to
pain hypersensitivity and short-term tolerance, a phenomenon encountered in
postoperative pain management by acute
opioid administration. The clinical management of
pain by
morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.