Neurochem. Int. Vol. 20, No. 4, pp. 463-468, 1992 Printed in Great Britain. All rights reserved

0197-0186/92 $5.00 + 0.00 Copyright © 1992 Pergamon Press Ltd

CRITIQUE THE EXCITATORY EFFECTS OF OPIOIDS LI-YEN MAE HUANG

Marine Biomedical Institute and Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX 77550, U.S.A.

Bramham proposed a hypothesis concerning the Since the direct effect of opioids is often inhibitory mechanism of long-term potentiation (LTP) at the (North, 1986; Tortella, 1988), disinhibition is the lateral perforant path (LPP)-dentate granule cell syn- most common mechanism used to account for the apse in the hippocampus. What sets this hypothesis excitatory action of opioids in the hippocampus and apart from others is the assumption that activation of other systems (Siggins and Zieglgansberger, 1981; opioid receptors is essential in the induction of LTP. Madison and Nicoll, 1988 ; Segal, 1988 ; Fields et al., The major experimental observations supporting the 1991). The direct actions of opioids, on the other hand, assumption are : naloxone introduced during the teta- is rarely considered. Bramham suggested that an nus blocks the LTP (Bramham et al., 1988) ; a selective increase in the intracellular calcium and second mess#-opioid agonist, PLO17, lowers the threshold for engers, as the result of the activation of 6-opioid recepLTP at LPP (Xie and Lewis, 1991) ; and endogeneous tors and non-NMDA receptors, facilitates LTP. He opioids are effectively released during high frequency did not elaborate on how 6-receptor activation, if it stimulation (Wagner et al., 1990 ; Caudle et al., 1991). results in the hyperpolarization of the postsynaptic Bramham's hypothesis is put forward to explain how cell, would induce LTP. The inconsistency would be opioid receptors participate in the generation of LTP. resolved if opioids can enhance the EPSP or excite Bramham assumed that 6-opioid receptors are located the cell directly. Although the evidence for a direct at the synaptic junction of LPP, and #-/r-opioid excitatory action of opioids in the hippocampus is not receptors are situated on the processes of GABAergic strong at the moment, the possibility should not be interneurons. Because D-2-amino-5-phosphono- dismissed. Opioids do excite neurons directly in many valaric acid (APV), a selective N-methyl-D-aspartate instances, and the idea may later prove to be impor(NMDA) receptor antagonist, blocks the population tant in understanding LTP. In this commentary, I will spike but has no effect on the excitatory postsynaptic present evidence, primarily from experiments perpotential (EPSP) (Xie and Lewis, 1991), Bramham formed on sensory neurons, to suggest that opioids further speculated that n o n - N M D A receptors are can excite neurons directly, and that the role of second located on the dendritic spine, and that a large fraction messengers is essential in considering the action of of NMDA-receptors are located on the dendritic opioids. shafts near the GABAergic terminals. When the high frequency simulation is applied to the LPP, excitatory LONG-TERM POTENTIATION IN CENTRAL amino acids, e.g. glutamate, and opioids are released NOCICEPTIVE NEURONS from the terminals. Bramham proposed that induction of LTP is faciliLong-term potentiation of synaptic transmission is tated by two mechanisms: (1) activation of 6-opioid a phenomenon occurring in many systems besides the receptors and non-NMDA receptors at the synapse hippocampus. In the nociceptive system, following excites granule cells directly; (2) activation of/~-/~c- tissue injury or repetitive stimulation of small diamopioid receptors depresses the excitability of the eter afferent fibers, the properties of central nocicepGABAergic interneurons, allowing the depolarization tive neurons undergo many long term changes, such of granule cell dendrites and activation of N M D A as an increased sensitivity to noxious stimuli, receptors to occur (i.e. a disinhibition mechanism). enlargement of the receptive field, a dramatic increase 463

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in the discharge of spinal neurons (wind-up), and initiation of a sustained potentiation in neuronal responses (Fields, 1987: Dubner, 1991). These changes are thought to be functionally important in the generation and maintenance of chronic pain (Dubner, 1991 Wilcox, 1991). One obvious parallel between LTP in the hippocampus and LTP in the nociceptive system is the requirement for activation of N M D A receptors (Collingridge and Lester, 1989; Dickenson, 1990; Madison et al., 1991; Woolf and Thompson, 1991). The sensitization of nociceptive spinal cord neurons can neither be induced nor maintained in the presence o1' an N M D A receptor antagonist (Dickenson, 1990 ; Woolf and Thompson, 1991 ). In addition, peripheral tissue injury causes an upregulation of dynorphin (Cho and Basbaum, 1988; ladarola et al., 1988 ; Nishimori et at., 1988 ; Ruda et al., 1988" Kajander et al., 1990), and temporal changes in l~-, 6-, and ~c-opioid receptor levels (Stevens et al., 1991). Opioids and excitatory amino acids participate in the long term changes in nociceptive neurons, just as in hippocampal neurons. OPIOIDS HAVE DIRECT EXCITATORY ACTIONS ON NEURONS

The effect of opioid peptides on neuronal excitability are generally thought to be inhibitory. Postsynaptically, #-, ~$- and K-opioid receptor agonists hyperpolarize the membranes by increasing potassium conductanees or by decreasing calcium conductances of neurons (Werz and MacDonald, 1982; William et a/., 1982 : Tsunoo el al., 1986 : Gross and MacDonald, 1987; Surprenant et al.. 1990; Tatsumi et al., 1990; Schroeder el a/., 1991 ; Wimpey and Chavkin, 1991). Presynaptically, opioid agonists reduce the release o1" substance P (SP) (Mudge et al., 1979), acetylcholine (Konishi et al., 1981 ; Mulder et al., 1984; Cherubini and North. 1985), [5-methionin]-enkephalin (metENK) (Xu and Gintzler. 1989: Gintzler and Xu, 1991), or norepinephrine (NE) (Schoffclmer and Mulder, 1984; Jackisch et al., 1986: Werling el a/., 1987). Thc action of opioids is far more complex than once thought. In dorsal root ganglion (DRG) explants, p-, 6-, and ~c-receptor agonists at I 10 nM lengthen the action potential (Crain and Shen, 1990). Since the somata of these cells do not receive synaptic inputs, the excitatory action of the opioids is clearly direct. Potassium channel blockers abolish the prolongation of the action potential elicited by the 6-/t-receptor agonist, DADLE, but have no effect on that elicited by the K-receptor agonist U-50,488H (Shen and Crain,

1989, 1990). These results are consistent with the idea that #- and 6-opioid receptor agonists decrease the conductance of potassium channels, and the 1,receptor agonist increases the conductance of calcium channels. The channel mechanism underlying this excitatory action of opioids remains to be confirmed. Shen and Crain (1989) further learned that postsynaptic action of opioids on DRG cells varies with concentration. In contrast to thc prolongation of action potential by low concentrations of opioid, action potential is shortened when HM concentrations ofopioids are used (Shcn and Crain, 1989 ; Crain and Shen, 1990). Moreover, the effect of opioids at times changes with the duration of treatment. For example, in visceral primary afferent neurons (no dosc ganglion cells), I nM morphine enhances calciumdependent components of the action potential, while 10 nM morphine depresses the amplitude or duration of the calcium-dependent spikes (Higashi et al., 1982). In 50% ot" the cells tested, morphine, at low concentration (1 nM), initially enhances and then depresses the calcium spikes. All of the morphine effects are naloxone blockable (Higashi el al., 1982). The presynaptic effects of morphine arc also complex. In myenteric plexus of guinea pig, p-, 6- or ~c-selective opioids at concentrations below 10 nM enhance electrically simulated release of met-ENK, but inhibit the release when the concentration of the agonist is raised above 10 100 nM (Xu and Gintzler, 1989 ; Gintzler and Xu, 1991). Suarez-Roca el al. (1991) examined the morphine effects on potassium-evoked release of SP from rat trigeminal nucleus over a wide range of concentrations (5 log units), and found that morphinc produces a multiphasic effect on the SP release. At I nM, morphine blocks SP release : at 100 300 nM, morphine enhances the release; at a low micromolar concentration (3 FIM), the morphine effcct is again inhibitory : and at 30 ILM, the morphine effect becomes excitatory. Naloxone. at 30 nM. blocks all the morphine effects. Suarez-Roca and Maixncr (1991) then studied the action of selectivc opioid receptor antagonists on the complex effects of morphine and found that the inhibition of SP release by 1 nM morphine is only affected by the selective H~-opioid receptor antagonist. The enhancement of SP release by 30 HM morphine is blocked by ~,-opioid receptor antagonists, and the effects on SP release by the intermediate concentrations of morphine (100 nM and 3 itM) are affected by re- and 6opioid receptors antagonists. These results show that the multiphasic effect of morphine on SP release is mediated by different subtypes of opioid receptors

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(Suarez-Roca et al., 1991 ; Suarez-Roca and Maixner, 1991).

and mediates the enhancement of met-ENK release (Gintzler and Xu, 1991).

SECOND MESSENGERS PLAY AN IMPORTANT ROLE

SUSTAINED POTENTIATION OF NMDA RECEPTOR-

A p-OPIOID RECEPTOR AGONIST PRODUCES A IN T H E O P I O I D ACTION

There is strong evidence that #-, ¢~- and I¢-opioid receptors are coupled to GTP-binding proteins ( G , G~ and Go) (Loh and Smith, 1990; Childers, 1991). Adenylate cyclase is one of the second messenger systems often associated with opioid receptors. 6-opioid receptors were found to inhibit adenylate cycles in NG108-15 cell by coupling to G~ (Abood et al., 1987; Childers, 1991). When purified ~t-opioid receptors were reconstituted with purified G~ and Go, the binding of a /2-opioid agonist, [D-AlaZ,MePhe4,gly-olS]en kephalin (DAGO), to the receptors was increased by 33- to 215-fold. This increase is abolished by addition of guanosine-5'-[?-thio]triphosphate, suggesting that /~-opioid is functionally coupled to G~ and Go (Ueda et al., 1988). The coupling between the K-opioid receptors and G~/Go has also been established (Childers, 1991). Electrophysiological evidence indicates that the opioid receptor-G protein coupling gives rise to changes in channel conductance. The inhibitory action of opioids are mediated by G~ or Go because pertussis toxin (PTX, a bacterial toxin that blocks activation of G~ and Go) abolishes the ability of/~and 6-opioid receptor agonists to increase potassium or to decrease calcium currents (Hescheler et al., 1987 ; Surprenant et al., 1990; Tatsumi et al., 1990). In DRG cells, the prolongation of action potentials by #- and 6-opioid receptor agonists is blocked by intracellular injection of cAMP-dependent protein kinase A inhibitor (PKAI) (Chen et al., 1988), or in cells pretreated with cholera toxin A (Crain and Shen, 1990). These results suggest that the excitatory action of opioids is mediated through G~, the activation of which increases the level of adenyl cyclase. The shortening of the action potential by opioids, on the other hand, is mediated by G~ or Go (Crain and Shen, 1990). G proteins are involved in the presynaptic action of opioids as well. Opioid-induced inhibition of NE and met-ENK release were regulated by PTX-sensitive G proteins (Schoffelmer et al., 1986; Childers, 1991; Gintzler and Xu, 1991). But, opioid-induced enhancement of met-ENK release is insensitive to PTX, indicating a different class of G protein is involved in transducing the response (Gintzler and Xu, 1991). Since cholera toxin abolish the enchancing effect of opioids, Gs is coupled to opioid receptors

MEDIATED GLUTAMATE

RESPONSES

In addition to direct action on ion channels, opioid peptides also modulate responses to the excitatory amino acid, glutamate, and its analogs. The 6-opioid receptor agonist, enkephalin, inhibits the glutamateevoked activity of spinal neurons (Barker et al., 1978 ; Willcockson et al., 1986). /~- and r-opioid receptor agonists, such as morphine and dynorphin, inhibit and/or excite glutamate-evoked responses of spinothalamic neurons (Willcockson et al., 1986). To determine how #-opioid receptor agonists modulate the glutamate responses, we have examined the interaction between glutamate and DAGO in rat spinal trigeminal neurons in thin medullary slice (Chen and Huang, 1991). DAGO, at 1 #M, enhances glutamateactivated and N-methyl-o-aspartate (NMDA)-activated currents, but does not affect kainate-activated currents. Furthermore, this enhancement of glutamate or NMDA-evoked responses can be blocked by APV, suggesting that DAGO acts only on NMDA receptors in trigeminal neurons. In the presence of naloxone, the change in the glutamate response by DAGO is minimal. The action of DAGO is direct because the same observation is obtained in isolated trigeminal neurons (unpublished observation). The effect of DAGO is long lasting (Chen and Huang, 1991). Once the glutamate-evoked response is elevated, it can last for 30-60 rain after removing DAGO from the bath solution. Similar results were also reported for isolated spinal dorsal horn neurons (Rusin and Randic, 1991). One difference is that in spinal neurons, DAGO at 10-100 nM causes an initial decrease in NMDA-activated currents followed by a sustained increase in N M D A responses after removal of DAGO. To determine the second messenger system which mediates this sustained action of DAGO, we studied the effect of intracellular protein kinase A (PKA) and protein kinase C (PKC) on glutamate-activated currents (Chen and Huang, 1991). PKA and PKAI do not mimic the effect of DAGO, suggesting that cyclic AMP-dependent protein kinase is not involved in the modulatory action of DAGO. On the other hand, intracellularly applied protein kinase C (PKC) mimics the action of DAGO, and a specific PKC inhibitor interrupts the sustained potentiation produced by DAGO (Chert and Huang, 1991). Thus, DAGO

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modulates N M D A receptor-mediated glutamate response t h r o u g h activation of PKC. W e propose that when the /t-opioid peptide binds to the receptor, it activates G proteins, causes the activity of P K C to rise, and leads to the e n h a n c e m e n t of N M D A receptormediated responses. I have given m a n y examples which show that opioids can exert direct excitatory actions either presynaptically or postsynaptically: a n d suggested that disinhibition is not the only mechanism that can mediate the opioid action. Since the effects of opioids depend on their concentration, it would be i m p o r t a n t to assess the opioid c o n c e n t r a t i o n at the terminal regions during tetanic stimulation. The a n t i b o d y microprobe technique developed by D u g g a n et al. (19901 may prove to be useful in determining the location and a m o u n t of e n d o g e n o u s opioids released from terminals of different pathways in the hippocampus. A study of the effects of opioids on ion currents in dissociated h i p p o c a m p a l n e u r o n s of specific regions should be helpful in determining a possible direct action o f opioids. In view o f o u r observation that a i,-opioid peptide can cause a sustained p o t e n t i a t i o n of N M D A receptor-mediated g l u t a m a t e response t h r o u g h activation of protein kinase C in trigeminal neurons, it will be interesting to test whether opioids m o d u l a t e N M D A - e v o k e d responses similarly in hipp o c a m p a l neurons.

Acknowledyements--The author thanks Dr W. D. Willis for comments and T. Fulford for preparing the manuscript. The author's work is supported by National Institutes grant NS23061, NS11255 and NS01050 (Research Career Development Award).

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