Molecular mechanism underlying the suppression of the morphine-induced rewarding effect and reduced sensitivity to morphine-induced antinociceptive action under chronic pain-like state

Abstract

This review attempts to summarize some of the mechanisms underlying the suppression of the morphine-induced rewarding effect and reduced sensitivity to morphine-induced antinociceptive action under a chronic pain-like state. It is of interest to note that animals with sciatic nerve ligation exhibited long-lasting thermal hyperalgesia and a significant increase in the levels of protein kinase Cγ (PKCγ)-, phosphorylated-conventional PKC (p-cPKC)-, brain-derived neurotrophic factor (BDNF)- and TrkB-like immunoreactivities (IR) on the ipsilateral side in the dorsal horn of the spinal cord, indicating a substantial increase in BDNF/PKC pathway under a neuropathic pain-like state. Intrathecal administration of inhibitors of PKC and a Trk-dependent tyrosine kinase and antibody to BDNF produced significant suppression of the thermal hyperalgesia evoked by sciatic nerve ligation. Astroglial hypertrophy/proliferation in the dorsal horn was also noted in sciatic nerve-ligated mice. As in nerve injury, animals tolerant to morphine-induced antinocicep-tion exhibited these changes. These findings suggest that the increase in the activity of spinal cPKC and the release of BDNF, or the spinal astrocytic response to under a neuropathic pain-like state may cause the suppression of morphine-induced antinociception.
A growing body of clinical evidence suggests that when opioid analgesics are used to control pain in patients, psychological dependence is not a major concern. It should be mentioned that animals with sciatic nerve ligation failed to exhibit morphine-induced place preference. Nerve injury also caused a significant decrease in the activity of extracellular signal-regulated kinase (ERK) on tyrosine hydroxylase (TH)-positive cells and a significant suppression of μ-opioid receptor (MOR)-mediated G-protein activation associated with an increase in G-protein-coupled receptor kinase 2 (GRK2) in GABA-containing cells in the ventral tegmental area (VTA). Furthermore, the inhibition of the ERK cascade in the VTA by treatment with specific inhibitors suppressed the morphine-induced rewarding effect. Moreover, pre-microinjection of the MOR antagonist, naltrexone (NTX), into the VTA reversed the changes by sciatic nerve ligation, indicating that a robust increase in released endogenous μ-opioids may be induced by sciatic nerve ligation, leading to the down-regulation of the MOR function. It should be pointed out that an inflammatory pain-like state following formalin injection to the paw significantly suppressed the morphine-induced rewarding effect and the increase in dopamine (DA) turnover in the limbic forebrain. These effects were almost reversed by pretreatment with the κ-opioid receptor antagonist, nor-binaltorphimine (nor-BNI). In addition, the decrease in the morphine-induced increase in extracellular levels of DA and its metabolites in the nucleus accumbens (N. Acc.) following formalin injection was reversed by the microinjection of a specific dynorphin A antibody into the N. Acc. These findings provide direct evidence that the reduction in MOR function and the persistent decrease in ERK activity of dopaminergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. In contrast, the endogenous κ-opioid system may be activated by chronic inflammatory nociception. The activation of the κ-opioidergic system may, in turn, inhibit DA release in the N. Acc., resulting in the suppression of the development of rewarding effects produced by morphine.