Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens

The present study was designed to further investigate the nature of feeding induced by opioid stimulation of the nucleus accumbens through an examination of the effects of intra-accumbens (ACB) opioids on macronutrient selection. In 3-hr tests of free-feeding (satiated) rats, intra-ACB administration of the mu receptor agonist D-Ala2,N,Me-Phe4, Gly-ol5-enkephalin (DAMGO; 0, 0.025, 0.25 and 2.5 micrograms bilaterally) markedly enhanced the intake of fat or carbohydrate when the diets were presented individually (although the effect on fat intake was much greater in magnitude). Intra-ACB injections of DAMGO, however, produced potent preferential stimulatory effects on fat ingestion with no effect on carbohydrate ingestion when both fat and carbohydrate diets were present simultaneously. Moreover, this selective stimulation of fat intake was independent of base-line diet preference and could be blocked by systemic injection of naltrexone (5 mg/kg). We also examined the effect of 24-hr food deprivation on the pattern of macronutrient intake in rats with access to both carbohydrate and fat. In contrast to the DAMGO-induced selective enhancement of fat intake, food deprivation significantly increased the intake of both diets to the same extent; however, in this case, only the stimulated fat intake was blocked by systemic naltrexone. Intra-ACB administration of DAMGO in hungry rats produced an effect similar to that observed in free-feeding rats; preference was strongly shifted to fat intake. Similarly, the opioid antagonist naltrexone (20 micrograms) infused directly into ACB preferentially decreased fat intake in hungry rats. These findings suggest that endogenous opioids within the ventral striatum may participate in the mechanisms governing preferences for highly palatable foods, especially those rich in fat.     

Selective opioid agonists modulate afferent transmission in the rat nucleus tractus solitarius

We examined the effects of agonists at mu, delta and kappa opioid receptors on neurons located in the nucleus tractus solitarius of the rat using whole-cell patch-clamp recordings in brainstem slices. The mu selective opioid agonist DAMGO hyperpolarized most neurons tested. This effect was associated with the activation of a K(+)-conductance. The effect of DAMGO tended to desensitize and was blocked by naloxone. Dynorphin A also produced this effect. However, the kappa-1-selective opioid agonist U-69593 and two delta-selective opioid agonists did not. DAMGO also depressed glutamate-mediated excitatory postsynaptic potentials and GABA-mediated evoked by stimulation of the tractus solitarius. Dynorphin A, U-69593 and delta-opioid agonists also reduced the excitatory postsynaptic potential, although they were less effective than DAMGO. The presynaptic inhibitory effects of DAMGO were also blocked by naloxone, but did not desensitize. These actions may help to explain the ability of opiates to modulate a variety of autonomic reflexes.     

Behavioral characterization of amygdala involvement in mediating intra-accumbens opioid-driven feeding behavior.

The present experiments were conducted to provide a more detailed behavioral analysis of the dissociable roles of the basolateral (BLA) and central nucleus (CeA) of the amygdala in mediating intra-accumbens (Acb) opioid-induced feeding of a high-fat diet. Confirming previous findings, temporary inactivation of the CeA with the GABAA agonist muscimol reduced DAMGO (D-Ala2-NMe-Phe4-Glyol5-enkephalin)-induced and baseline food intake, whereas intra-BLA muscimol selectively blocked only DAMGO-induced food intake, leaving baseline feeding intact. However, although inactivation of the BLA reduced DAMGO-induced food intake to control levels, this treatment led to exaggerated number and duration of food hopper entries after food intake had ended. A subsequent experiment under conditions of limited access to the diet found the identical pattern of behavior following intra-Acb administration of DAMGO, regardless of whether the BLA was inactivated. Last, BLA inactivation was shown to have no influence on feeding driven by a state of negative-energy balance (24-hr food deprivation), demonstrating a specific influence of the BLA on opioid-driven feeding. These findings suggest that BLA mediates palatability-driven feeding and that this influence is particular to the consummatory act of ingestion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Medullary pathways of cardiovascular responses to 5-HT2 and 5-HT3 receptor stimulation in the rat nucleus tractus solitarius

As previously found for the baroreceptor reflex, microinjection of kynurenic acid (KYN, 2 nmol), a glutamate receptor antagonist, into the caudal ventrolateral medulla (CVL) blocked the hypotension and bradycardia elicited by microinjections of a 5-HT2 receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5 pmol) into the nucleus tractus solitarius (NTS). In addition, as previously observed with the sympathetic chemoreflex response, microinjections of KYN into the RVI, blocked the increase in blood pressure elicited by microinjections of 1-m-(chlorophenyl)-biguanide (1200 pmol), a 5-HT1 receptor agonist, into the NTS. These results suggest that medullary pathways involved in the responses to 5-HT2 and 5-HT3 receptor stimulation in the NTS are similar to those that mediate the baroceptor and chemoreceptor reflex responses, respectively.     

Beta-endorphin response to exercise. An update

Opioid receptor subtype antagonists differentially alter food intake under deprivation (24 h), glucoprivic (2-deoxy-D-glucose, 500 mg/kg, i.p.) or palatable (10% sucrose) conditions with mu (beta-funaltrexamine) and kappa (nor-binaltorphamine), but not delta1 ([D-Ala2,Leu5,Cys6]enkephalin) opioid antagonists reducing each form of intake following ventricular microinjection. Both mu and kappa opioid antagonists microinjected into either the hypothalamic paraventricular nucleus or the nucleus accumbens reduce intake under deprivation and glucoprivic conditions. Palatable intake is reduced by both antagonists in the paraventricular nucleus, but only mu antagonists are active in the accumbens. Food intake is stimulated by mu and delta, but not kappa, opioid agonists microinjected into the ventral tegmental area. The present study examined whether food intake under either deprivation, glucoprivic or palatable conditions was altered by bilateral administration of general (naltrexone), mu, kappa, delta1 or delta2 (naltrindole isothiocyanate) opioid antagonists into the ventral tegmental area. Deprivation (24 h)-induced feeding was significantly reduced by high (50 microg), but not lower (10-20 microg) doses of naltrexone (21%), and by delta2 (4 microg, 19%) antagonism in the ventral tegmental area. 2-Deoxy-D-glucose (500 mg/kg, i.p.)-induced hyperphagia was significantly reduced by high (50 microg), but not lower (20 microg) doses of naltrexone (64%), and by delta2 (4 microg, 27%) antagonism in the ventral tegmental area. Sucrose (10%) intake was significantly reduced by naltrexone (20-50 microg, 25-39%) and delta2 (4 microg, 25%) antagonism in the ventral tegmental area. Neither mu, kappa nor delta1 antagonists were effective in reducing any form of intake following microinjection into the ventral tegmental area. These data indicate that the ventral tegmental area plays a relatively minor role in the elicitation of these forms of food intake, and that delta2, rather than mu, kappa or delta1 opioid receptors appear responsible for mediation of these forms of intake by this nucleus.     

Amylin reduces food intake more potently than calcitonin gene-related peptide (CGRP) when injected into the lateral brain ventricle in rats

Amylin and the structurally and functionally related peptide calcitonin gene-related peptide (CGRP) have been shown to reduce food intake in rats. The aim of the present study was to compare the anorectic potency of both peptides over a wide dose range when administered into the lateral brain ventricle (ICV). Furthermore, we also tested the influence of a lesion in the area postrema/nucleus of the solitary tract (AP/NTS) region on the anorectic effects of amylin and CGRP after ICV administration because AP/NTS lesion has been shown to reduce the anorectic effects of both peptides when injected intraperitoneally (IP). Amylin [1-510 pmol/rat (0.004-2 microg/rat) ICV] and CGRP [1-131 pmol/rat (0.004-0.5 microg/rat) ICV] dose-dependently reduced food intake in food-deprived rats. At a dose of 26 pmol/rat (0.1 microg/rat), amylin almost completely suppressed food intake for 1 h after injection. Amylin [EC50 = 2 pmol/rat (0.007 microg/rat)] was markedly more potent than CGRP [57 pmol/rat (0.215 microg/rat)] with regard to its anorectic effect. A lesion in the AP/NTS region did not influence the anorectic effects of amylin and CGRP after administration into the lateral ventricle. It is concluded that amylin is more potent than CGRP in reducing food intake after administration into the lateral brain ventricle. Receptors in the forebrain may mediate the anorectic effects of both peptides when administered via this route.     

Opioids activate G proteins in REM sleep-related brain stem nuclei of rat

Mu opioid receptors within the pontine reticular formation contribute to opioid-induced rapid eye movement (REM) sleep inhibition. Mu receptors are coupled to guanine nucleotide binding (G) proteins and this study tested the hypothesis that the micro opioid agonist [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) would activate G proteins in rat brain stem nuclei known to regulate REM sleep. In vitro autoradiography of DAMGO-stimulated [35S]GTPgammaS binding showed that, compared with basal [35S]GTPgammaS binding, DAMGO significantly increased G protein activation in the nucleus pontis oralis (56.2%), nucleus pontis caudalis (57.3%), laterodorsal tegmental nucleus (75.8%), pedunculopontine tegmental nucleus (72.4%), nucleus locus coeruleus (77.2%) and dorsal raphe nucleus (73.4%). DAMGO stimulation of [35S]GTPgammaS binding in nuclei regulating REM sleep suggests that opioid-induced REM sleep inhibition involves activation of G proteins.     

Treatment of chronic allodynia in spinally injured rats: effects of intrathecal selective opioid receptor agonists

We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.     

Induction of Fos-like immunoreactivity by opioids in guinea-pig brain

In the present study the effects of intracerebroventricular (i.c.v.) administration of 100 nmol of morphine, the selective mu-receptor agonist DAMGO, the delta-receptor agonist DPDPE and the kappa-receptor agonist U50,488H, on the induction of Fos-like immunoreactivity (Fos-LI) in the guinea-pig brain were investigated using immunohistochemical techniques. Guinea-pigs given i.c.v. injection of opioids showed marked increases in the number of Fos-LI nuclei within a large number of brain regions, several of which, including hypothalamic nuclei, paraventricular thalamic nucleus, the amygdala, periaqueductal gray, superior and inferior colliculi, the piriform and entorhinal cortices, have been shown to be activated under stressful or aversive conditions. Pretreatment with the opioid antagonist, naltrexone, before administration of morphine or U50,488H, inhibited Fos-LI induction indicating that the effects of the opioids were mediated by opioid receptors. U50,488H administration resulted in higher numbers of Fos-LI stained neurons compared to morphine in most regions other than the nucleus accumbens and interpeduncular nucleus. Morphine and DAMGO produced significantly higher numbers of Fos-LI neurons in the nucleus accumbens shell region than U50,488H, which may reflect the more powerful reinforcing/rewarding effects of mu-receptor agonists. Thus the present study supports a critical role for the nucleus accumbens shell region in the reinforcing/rewarding effects of opioids.     

Role of nitric oxide in the nucleus of the solitary tract of rats

We have determined the role of nitric oxide (NO) in the nucleus of the solitary tract (NTS) of normotensive Wistar rats. The unilateral microinjection of Nomega-nitro-l-arginine methyl ester (10 nmol) to block the synthesis of NO into the NTS significantly decreased the arterial pressure, heart rate (HR) and renal sympathetic nerve activity (RSNA) (-19+/-2 mmHg, -23+/-5 beats/min, -30+/-2%, respectively). The microinjection of carboxy-2-phenyl-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide (Carboxy PTIO) (trapper of NO; 0.1 nmol) into the NTS also decreased arterial pressure and RSNA. Conversely, the microinjection of Et2N[N(O)NO]Na (NOC 18) (NO donor; 10 nmol) caused increases in arterial pressure, HR and RSNA (+14+/-2 mmHg, +11+/-2 beats/min, +38+/-7%, respectively), which was inhibited by the pre-microinjection of Carboxy PTIO (0.1 nmol). On the other hand, not only l-arginine (10 nmol) but also d-arginine (10 nmol), which is inactive to produce NO, significantly decreased the arterial pressure and RSNA. These results suggest that (1) NO acts at the NTS to increase the arterial pressure and RSNA, and (2) the microinjection of l-arginine as well as d-arginine led to decreases in arterial pressure and RSNA that were not mediated by the formation of NO in the NTS.     

Enterostatin actions in the amygdala and PVN to suppress feeding in the rat

The pentapeptide enterostatin (ENT) inhibits feeding after injection into the cerebral ventricles. To localize the central sites of action of ENT, the peptide (0.01 to 3.3 nM) was microinjected into several brain regions and the intake of a high fat diet was measured. The results show that ENT injection in the paraventricular nucleus (PVN) or the amygdala (AMYG) produced a bi-phasic dose related feeding response, low doses of ENT inhibited feeding while higher dose had no effect. The effective dose to inhibit feeding in the AMYG was 10 fold lower than that in the PVN. No changes in food intake were observed after ENT injection into the ventromedial hypothalamus and nucleus tractus solitarius. The data provide further support that there are targets in the CNS for ENT and suggest that central ENT function is site specific.     

Lewis and Fischer rats: a comparison of dopamine transporter and receptors levels

We have reported that rats increased their intake of food, but not water, following an intraperitoneal injection of MK-801, a non-competitive antagonist of N-methyl-d-aspartate (NMDA)-activated ion channels. The antagonist appears to specifically interfere with signals that participate in meal termination (satiety), thereby prolonging the meal and increasing its size. The anatomical site at which MK-801 acts to increase food intake is not known. However, vagal sensory neurons are known to participate in satiation for food. Furthermore, NMDA receptor immunoreactivity is present in the caudal nucleus of the solitary tract (NTS) where vagal sensory fibers terminate. Therefore, we hypothesized that MK-801 might increase food intake by blocking NMDA receptors in the NTS. To test this hypothesis, we microinjected MK-801 directly into the hindbrain, immediately prior to a deprivation-induced meal of 15% sucrose. We found that sucrose intake was significantly increased following injection of MK-801 (2 microgram/3 microliter) into the fourth ventricle. When MK-801 was injected directly into the caudomedial NTS, intake was increased significantly by doses as small as 198 ng/30 nl, while equivalent injections into other hindbrain areas or the fourth ventricle did not increase food intake. These data are consistent with control of food intake by endogenous glutamate and NMDA-type glutamate receptors located in the caudomedial NTS.     

Reversible lesions of the nucleus of the solitary tract attenuate the memory-modulating effects of posttraining epinephrine.

Male rats implanted with cannula tips placed above the nucleus of the solitary tract (NTS) were trained to obtain food pellets placed in 2 arms of a Y-maze and then given a footshock in 1 arm of the maze. Ss then received bilateral injections of lidocaine or buffer into the NTS and peripheral injections of saline or epinephrine (0.01 or 0.05 mg/kg, intraperitoneally [ip]). Two tests were given 24 and 48 hrs after training to assess retention in the presence and absence of contextual cues (the stainless steel floor) associated with the footshock training trial. Epinephrine (0.05 mg/kg) produced a significant enhancement in retention, which was attenuated by injections of lidocaine into the NTS. These findings indicate that the NTS is involved in mediating the memory-modulating effects of peripheral epinephrine and that such effects are initiated at least in part by activation of vagal afferents projecting to the NTS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid receptor blockade during prenatal life modifies postnatal behavioral development

The ontogeny of physical characteristics, spontaneous motor, and sensorimotor behaviors of preweaning rats, as well as ambulation and emotionality at weaning (day 21) were studied in rats exposed to 50 mg/kg naltrexone (NTX) or saline (controls) daily throughout gestation by maternal administration; all animals were cross-fostered to untreated mothers at birth. Morphine challenge tests and nociceptive measures revealed that this dosage of opioid antagonist blocked opioid receptors for 24 h. At birth and weaning, animals in the NTX group weighed 12 and 20%, respectively, more than control offspring. The age at which a specific physical characteristic, spontaneous motor behavior, or reflex initially appeared and the age at which 100% of the animals demonstrated a particular characteristic/behavior often were accelerated in animals prenatally exposed to NTX. The frequency of ambulation was subnormal in the NTX group, and the frequency and/or incidence of rearing, grooming, wet-dog shakes, and defecation were reduced from normal levels in these opioid antagonist-exposed rats. These results imply that interactions of endogenous opioid systems during embryogenesis are determinants of somatic, physical, and behavioral development in postnatal life.     

Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs

We examined whether opioids, especially morphine, would centrally elicit scratching in mice and determined some characteristics of the scratch-inducing action of opioids. When intracisternally (i.c.) injected, morphine (0.1-3 nmol/mouse) produced a dose-dependent increase in scratching of the face, but not of the ears, head and body trunk. When injected intradermally into the rostral part of the back, morphine (at most potent i.c. dose of 3 nmol/mouse or higher) did not increase the scratching of the injected site. Facial scratching of the mouse induced by i.c. injection of morphine (0.3 nmol/mouse) was almost abolished by distraction and by naloxone (1 mg/kg, s.c.). [D-Ala2, N-Me-Phe4, Gly5-ol]Enkephalin (DAMGO) (0.03-2 nmol), but not [D-Pen2,5]enkephalin (DPDPE) and U-50,488, dose-dependently elicited facial scratching by i.c. injection. These results suggest that morphine and DAMGO increased facial scratching, probably mediated by central opioid mu-receptors in mice, and such scratching was due to a sensation, probably itching. The present animal model may be useful for analyzing opioid-mediated central itching.     

Cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats

It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of L-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester significantly attenuated the depressive and bradycardic effects of adenosine. These results demonstrate a reciprocal attenuation of adenosine receptor antagonist and NO synthase inhibitor on L-arginine and adenosine responses, respectively, in the NTS and implicate an interaction between NO and adenosine in central cardiovascular regulation.     

Role of central mu-opioid receptors in the modulation of nitric oxide production by splenocytes

Previous studies have shown that administration of morphine results in alterations of splenic macrophage nitric oxide production. The present studies were conducted to determine the subtype of opioid receptor involved in the modulation of macrophage nitric oxide production. Moreover, the present work was directed at determining whether nitric oxide production is regulated through opioid receptors in the central nervous system (CNS) or via opioid receptors found directly on splenocytes. The study shows that intracerebroventricular (i.c.v.) administration of the mu-selective opioid agonist, DAMGO, to rats dose-dependently increases the production of nitric oxide by splenocytes stimulated with toxic shock syndrome toxin (TSST-1). The effect of DAMGO is blocked by prior i.c.v. administration of N-methylnaltrexone. In contrast, i.c.v. administration of the kappa-selective agonist, U69,593, and the delta-selective agonist, DPDPE, have no significant effect on the production of nitric oxide. Furthermore, the in vitro administration of DAMGO, DPDPE, or U69,593 to splenocytes cultures does not significantly alter the production of nitric oxide by splenocytes. In addition, the present work shows that elevation of nitric oxide production by i.c.v. administration of DAMGO produces functional changes in splenic lymphocytes. Collectively, these results indicate that mu-opioid receptors within the CNS are involved in the regulation of splenic nitric oxide production.     

Upregulation of imidazoline receptors in the medulla oblongata accounts for the enhanced hypotensive effect of clonidine in aortic barodenervated rats

The present study tested the hypothesis that an upregulation of the imidazoline receptor in the rostral ventrolateral medulla (RVLM) of aortic barodenervated (ABD) rats may account for the enhanced hypotensive effect of clonidine. In vitro autoradiographic radioligand binding studies were utilized to investigate the binding characteristics of imidazoline receptors in the RVLM and nucleus tractus solitarius (NTS), areas that play critical roles in cardiovascular regulation and elicitation of clonidine responses. ABD but not sham operation (SO) caused immediate and significant (P < 0.05) increases in mean arterial pressure (MAP) and heart rate (HR) and an impairment of the baroreflex-mediated HR response (baroreflex sensitivity, BRS). Two days after ABD, these parameters, except BRS, subsided to near-control (SO) levels. Intracisternal (i.c.) administration of clonidine (0.1 micrograms) elicited a 3-fold greater decrease in BP of conscious ABD compared with SO rats (-20.3 +/- 2.6 vs. -7.4 +/- 0.9 mmHg) thus demonstrating the ability of ABD to enhance centrally-mediated hypotensive responses. Autoradiographic visualization of brain sections obtained from separate groups of ABD and SO rats 48 h after surgery preincubated with [3H]idazoxan (2.5-3.5 nM) showed that [3H]idazoxan binding in RVLM, middle NTM (mNTS) and rostral NTS (rNTS) was saturable and of high affinity. Uneven distribution of imidazoline binding sites was evident since in control (SO) rats, Scatchard analysis of binding data revealed similar densities (Bmax) of [3H]idazoxan binding sites in the RVLM and mNTS versus significantly higher density in the rNTS. In ABD rats, the binding dissociation constant (Kd) was significantly decreased in both the RVLM (8.1 +/- 3.1 vs. 21.4 +/- 5.0 nM) and rNTS (12.3 +/- 1.3 vs. 18.6 +/- 3.1 nM) compared with SO rats while the Bmax was not affected. This finding suggests an increased receptor affinity in the RVLM and rNTS of barodenervated rats. The mNTS of ABD rats exhibited significant increases in the Bmax (861 +/- 96 vs. 570 +/- 87 fmol/mg protein) compared with values of SO rats but the receptor affinity was not affected. It is concluded that: (i) aortic baroreceptors exert a tonic inhibitory influence on central imidazoline receptor function; and (ii) the enhanced hypotensive effect of clonidine in conscious ABD rats may be accounted for by the increased affinity of the medullary imidazoline receptors particularly in the RVLM.     

Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity

Motor activity elicited pharmacologically from the nucleus accumbens by the mu-opioid receptor agonist D-Ala-Tyr-Gly-NMePhe-Gly-OH (DAMGO) is augmented in rats sustaining dopamine depletions. GABAergic projections from the nucleus accumbens to ventral pallidum and ventral tegmental area (VTA) are involved because stimulation of GABAB receptors in the VTA (by baclofen) or GABAA receptors in the ventral pallidum (by muscimol) inhibit the motor response induced by the microinjection of DAMGO into the nucleus accumbens. The present study was done to determine which of these projections is mediating the augmented DAMGO-induced motor activity that follows 6-hydroxydopamine lesions of the nucleus accumbens. The inhibition of DAMGO-induced activation by pallidal injections of muscimol was markedly attenuated in lesioned animals, whereas the inhibition by VTA injections with baclofen was greatly enhanced. A similar switch in emphasis from pallidal to mesencephalic efferents was not observed for dopamine-induced motor activity, because muscimol microinjections inhibited the response elicited by dopamine microinjection into the nucleus accumbens in all subjects. The stimulation of mu-opioid receptors in the ventral pallidum also elicits motor activation, and this is blocked by baclofen microinjection into the VTA. However, after dopamine depletion in the nucleus accumbens, baclofen in the VTA was ineffective in blocking the motor response by DAMGO in the ventral pallidum. These data reveal that dopamine depletion in the nucleus accumbens produces a lesion-induced plasticity that alters the effect of mu-opioid receptor stimulation on efferent projections from the nucleus accumbens and ventral pallidum.     

Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats

Neuropathic pains have often been classified as opioid-resistant. Here, spinal (intrathecal) actions of morphine and nonmorphine opioids have been studied in a nerve ligation model of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Nerve-injured animals exhibited allodynia that was stable for up to 6 weeks after the surgery. Morphine did not alter allodynia at doses up to 300 nmol (100 micrograms). In contrast, [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), a high-efficacy mu opioid agonist, produced a significant, dose-related antiallodynic action. [D-Ala2, Glu4]deltorphin (delta agonist) produced a significant antiallodynic effect only at 300 nmol, reaching approximately 70% of the maximum. Coadministration of morphine with a dose of [D-Ala2, Glu4]deltorphin, which was inactive alone, produced a significant and long-lasting antiallodynic action that was antagonized by NTI (delta receptor antagonist); NTI alone had no effect. Although blockade of cholecystokinin-B (CCKB) receptors with L365,260 did not produce effects alone, a significant antiallodynic action was observed when coadministered with morphine; this elevation of nociceptive threshold was abolished by NTI. The finding that DAMGO, but not very large doses of morphine, produced antiallodynic actions suggests that the ability of mu opioids to alleviate the allodynia is related, in part, to efficacy at postsynaptic mu receptors. At an inactive dose, a delta agonist or a CCKB antagonist enhanced morphine antiallodynic efficacy in an NTI-sensitive fashion. CCKB receptor blockade may enhance endogenous enkephalin actions, resulting in enhancement of morphine efficacy through a mu-delta receptor interaction.