Dynorphin/kappa Opioid Receptor Research Articles

Trigeminal injury causes kappa opioid-dependent allodynic, glial and immune cell responses in mice.

BackgroundThe dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR-/-) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ganglion (TG).ResultsIn KOR-/- mice or norBNI-treated mice, the number of proliferating cells in the Vp was significantly less than in WT mice, whereas cell proliferation was enhanced in TREZ and TG. The majority of the proliferating cells were nestin positive stem cells or CD11b positive microglia in the Vp and macrophages in the TG. GFAP-positive astrocytes made a clear borderline between the CNS and the PNS in TREZ, and phosphorylated KOR staining (KOR-p) was detectable only in the astrocytes in CNS in WT mice but not in KOR-/- or norBNI-treated mice.ConclusionsThese results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies.

Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2.

Earlier studies identified the dynorphin-kappa opioid receptor (KOR) system as a critical mediator of dysphoria-induced aversion after repeated stress exposure, but the molecular signaling mechanisms were not fully characterized. In this study we report that repeated forced swim stress caused a significant phosphorylation of extracellular signal-regulated kinase (ERK)1/2 a mitogen-activated protein kinase (MAPK) in both the caudate and nucleus accumbens regions of the mouse striatum. Activation was blocked by the KOR antagonist, norbinaltorphimine, and absent in KOR knockout mice. In contrast to p38-MAPK activation by stress-induced dynorphin release, KOR-mediated ERK1/2 phosphorylation was not dependent on G-protein coupled receptor kinase 3 expression. These results indicate stress-induced activation of the dynorphin-KOR systems activates ERK1/2 MAPK signaling, and this may contribute to the behavioral responses to repeated stress exposure.

Stress‐induced dysphoria is encoded by the Dynorphin‐Kappa Opioid system

Sustained stressful experience can induce despair and increase the risk of clinical depression and drug abuse. We found that repeated exposure of mice to stress (forced swim or social‐defeat) activated the dynorphin‐kappa opioid receptor system to produce analgesia, immobility, sensitization of the reward system to cocaine, and reinstatement of extinguished cocaine‐place preference. The cellular and molecular basis of these responses were described in a series of studies demonstrating that chronic stress evoked CRF/Urocortin release and subsequent CRF‐R2 receptor mediated dynorphin release. Surprisingly, aversion caused by stress and CRF were blocked by disruption of the dynorphin kappa opioid system. Dynorphin‐induced dysphoria was found to be mediated by p38 MAPK activated through a GRK3/arrestin dependent mechanism. Stress‐induced release of dynorphin activates kappa receptors broadly in brain. In particular, repeated stress caused activation of both KOR and p38 MAPK co‐expressed in GABAergic neurons. The p38 inhibitor SB203580 selectively blocked dynorphin‐induced aversion. The convergence of stress‐induced aversion on the dynorphin system was unexpected and implicates dynorphin activation of p38 MAPK signaling as a key component mediating the aversive properties of stress.

Which Opioid Receptor Mechanism Modulates Feeding?

There is substantial evidence for the role of endogenous opioid peptides in the regulation of appetite. This communication examines the possible opioid peptide mechanism(s) which are involved in appetite regulation. In the rat, activation of both the dynorphin-kappa opioid receptor and the beta-endorphin-epsilon opioid receptor appear to enhance feeding, most probably acting in different areas of the central nervous system. It also appears that rats may have a mu anorectic system. Too few studies have been undertaken to define whether the delta or sigma receptor systems are also involved in feeding responses. It is becoming apparent that a great deal of species diversity exists in the feeding responses to opiates, making it difficult to extrapolate the results obtained in rats to other species. In humans, studies with naloxone suggest an opioid sensitive feeding system which possibly is specifically involved in the regulation of carbohydrate uptake. In addition, we report here preliminary data suggesting the presence of a mu anorectic system in humans. Thus, analogous to the findings for the role of opioid receptors in analgesia, it appears that multiple opioid receptors may be involved in appetite regulation, each receptor relating to a different aspect of feeding.

Involvement of dynorphin and the kappa opioid receptor in feeding

Dynorphin-(1–17) produces a highly specific increase in food ingestion. Similar enhancement of food ingestion is found with dynorphin fragments (1–10), (1–11), (1–13) and (3–13) but not with (1–8) and (1–9). Dynorphin B (rimorphin) also enhances food intake. The highly specific kappa agonist U-50,488 also enhances food intake as do a number of other kappa-opiate receptor agonists. These studies provided further support for the role of a highly specific dynorphin-kappa opioid receptor in the modulation of feeding.