Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain.

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

Direct bidirectional µ-opioid control of midbrain dopamine neurons.

The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic µ-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 µM) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 µM, n = 5) and ω-agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca(2+) channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ± 7 mV and inhibitions were blocked by the K(+) channel blocker BaCl2 (100 µM, n = 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons.

Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry.

Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward-valuation circuitry.

Opioid modulation of ventral pallidal afferents to ventral tegmental area neurons.

Activation of mu opioid receptors within the ventral tegmental area (VTA) can produce reward through the inhibition of GABAergic inputs. GABAergic neurons in the ventral pallidum (VP) provide a major input to VTA neurons. To determine the specific VTA neuronal targets of VP afferents and their sensitivity to mu opioid receptor agonists, we virally expressed channel rhodopsin (ChR2) in rat VP neurons and optogenetically activated their terminals in the VTA. Light activation of VP neuron terminals elicited GABAergic IPSCs in both dopamine (DA) and non-DA VTA neurons, and these IPSCs were inhibited by the mu opioid receptor agonist DAMGO. In addition, using a fluorescent retrograde marker to identify VTA-projecting VP neurons, we found them to be hyperpolarized by DAMGO. Both of these actions decrease GABAergic input onto VTA neurons, revealing two mechanisms by which endogenous or exogenous opioids can activate VTA neurons, including DA neurons.

Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain.

In addition to their well-established role in signaling rewarding outcomes and reward-predictive cues and in mediating positive reinforcement, there is growing evidence that nucleus accumbens (NAc) neurons also signal aversive events and cues that predict them. Here we use diffusion tractography to subdivide the right NAc into lateral-rostral (putative core, pcore) and medial-caudal (putative shell, pshell) subdivisions in humans. The two subregions exhibited differential structural connectivity, based on probabilistic tractography, to prefrontal cortical and subcortical limbic regions. We also demonstrate unique roles for each of the two subdivisions for monetary reward and thermal pain perception tasks: pshell signaling impending pain and value predictions for monetary gambles and pcore activating with anticipation of cessation of thermal pain (signaling reward value of analgesia). We examined functional connectivity for resting state, monetary reward, and thermal pain tasks, and for all three conditions observed that pcore and pshell of right NAc exhibit distinct patterns of synchrony (functional connectivity) to prefrontal cortical and subcortical limbic targets within the right hemisphere. To validate the NAc segregation, we mirrored the coordinates of right NAc pcore and pshell onto the left hemisphere and examined structural and resting state connectivity in the left hemisphere. This latter analysis closely replicated target-specific connections we obtained for the right hemisphere. Overall, we demonstrate that the human NAc can be parceled based on structural and functional connectivity, and that activity in these subdivisions differentially encodes values for expected pain relief and for expected monetary reward.

Capturing the aversive state of cephalic pain preclinically.

OBJECTIVE: Preclinical evaluation of headache by behavioral assessment of reward from pain relief. METHODS: Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. RESULTS: Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury. INTERPRETATION: Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.

Intra-VTA deltorphin, but not DPDPE, induces place preference in ethanol-drinking rats: distinct DOR-1 and DOR-2 mechanisms control ethanol consumption and reward.

BACKGROUND: While there is a growing body of evidence that the delta opioid receptor (DOR) modulates ethanol (EtOH) consumption, development of DOR-based medications is limited in part because there are 2 pharmacologically distinct DOR subtypes (DOR-1 and DOR-2) that can have opposing actions on behavior. METHODS: We studied the behavioral influence of the DOR-1-selective agonist [D-Pen(2) ,D-Pen(5) ]-Enkephalin (DPDPE) and the DOR-2-selective agonist deltorphin microinjected into the ventral tegmental area (VTA) on EtOH consumption and conditioned place preference (CPP) and the physiological effects of these 2 DOR agonists on GABAergic synaptic transmission in VTA-containing brain slices from Lewis rats. RESULTS: Neither deltorphin nor DPDPE induced a significant place preference in EtOH-naïve Lewis rats. However, deltorphin (but not DPDPE) induced a significant CPP in EtOH-drinking rats. In contrast to the previous finding that intra-VTA DOR-1 activity inhibits EtOH consumption and that this inhibition correlates with a DPDPE-induced inhibition of GABA release, here we found no effect of DOR-2 activity on EtOH consumption nor was there a correlation between level of drinking and deltorphin-induced change in GABAergic synaptic transmission. CONCLUSIONS: These data indicate that the therapeutic potential of DOR agonists for alcohol abuse is through a selective action at the DOR-1 form of the receptor.

Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell.

Suppression of ill-timed or competing actions optimizes goal-directed behaviors. Diminished inhibitory control over such actions is a central feature of such disorders as impulsivity, obesity, and drug addiction. The ventromedial prefrontal cortex (vmPFC) is involved in suppression of unreinforced actions. Using reversible inactivation in rats, we demonstrate that vmPFC activity is also required for inhibition of unreinforced actions extinguished during learning of a cued appetitive task and that behavioral disinhibition following vmPFC inactivation depends on dopamine signaling in nucleus accumbens shell (NAcS). Combining electrophysiological recording in NAcS with vmPFC inactivation in rats reveals two neural mechanisms by which vmPFC inhibits unreinforced actions. The first is by suppressing phasic excitations that promote behavioral cue responding. The second is by increasing the basal firing of NAcS neurons that tonically inhibit reward seeking. These results identify the vmPFC and the NAcS as critical elements of the circuits relevant to suppression of inappropriate actions.

Ventral tegmental area glutamate neurons: electrophysiological properties and projections.

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2(+) VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (I(h)) than more lateral dopamine neurons and less consistent inhibition by dopamine D(2) receptor agonists. In addition, VGLUT2(+) VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2(+) projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons.

Dopamine, corticostriatal connectivity, and intertemporal choice.

Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.

International Association for the Study of Pain publications over the 50-year span.

ABSTRACT: The International Association for the Study of Pain (IASP) has a 50-year history of publishing educational and research materials, ranging from traditional print format books, journals, and other informational formats to online and electronic formats. Here we provide a historical overview of IASP publications and reflections from the perspective of 5 former or current Editors-in-Chief.

Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition.

The nucleus accumbens (NAc) is involved in many reward-related behaviors. The NAc has two major components, the core and the shell. These two areas have different inputs and outputs, suggesting that they contribute differentially to goal-directed behaviors. Using a discriminative stimulus (DS) task in rats and inactivating the NAc by blocking excitatory inputs with glutamate antagonists, we dissociated core and shell contributions to task performance. NAc core but not shell inactivation decreased responding to a reward-predictive cue. In contrast, inactivation of either subregion induced a general behavioral disinhibition. This reveals that the NAc actively suppresses actions inappropriate to the DS task. Importantly, selective inactivation of the shell but not core significantly increased responding to the nonrewarded cue. To determine whether the different contributions of the NAc core and shell depend on the information encoded in their constituent neurons, we performed electrophysiological recording in rats performing the DS task. Although there was no firing pattern unique to either core or shell, the reward-predictive cue elicited more frequent and larger magnitude responses in the NAc core than in the shell. Conversely, more NAc shell neurons selectively responded to the nonrewarded stimulus. These quantitative differences might account for the different behavioral patterns that require either core or shell. Neurons with similar firing patterns could also have different effects on behavior due to their distinct projection targets.

Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area.

The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA(A) or GABA(B) receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA(A) receptors.

A pause in nucleus accumbens neuron firing is required to initiate and maintain feeding.

Nucleus accumbens (NAc) inactivation increases food intake, indicating that NAc neurons exert ongoing inhibition of feeding. We previously described a subpopulation of NAc neurons that pause during sucrose licking and proposed that the pause permits consumption. We tested this hypothesis by first recording NAc neurons during sucrose consumption, and then electrically stimulating through the same electrodes. A large proportion of NAc shell and core neurons were inhibited during sucrose consumption, and local electrical stimulation abruptly interrupted licking. Effective stimulation sites were more anterior than ineffective sites in NAc. At low stimulus intensities, licking resumed immediately on stimulation offset. The latency to lick resumption from NAc neuron inhibition onset ( approximately 460 ms) was very similar to that after electrical stimulation offset ( approximately 440 ms). These results directly support the hypothesis that a significant subpopulation of NAc neurons inhibit palatable food consumption and that a pause in their firing is required to initiate and maintain consumption.

A novel opioid receptor-mediated enhancement of GABAA receptor function induced by stress in ventral tegmental area neurons.

Opioid receptors are G-protein-coupled receptors (GPCRs) that modulate synaptic function. Depending upon their nervous system site of action, opioid receptor agonists alter food consumption, pain perception, responses to stress, and drug reward. Opioid receptors signal primarily via G(i/o)-proteins that modulate ion channels to directly inhibit neurons or decrease neurotransmitter release from nerve terminals. Here we report that following stress, activating δ opioid receptors (DORs) on midbrain ventral tegmental area (VTA) neurons causes a novel synaptic effect: the augmentation of GABA(A) receptor (GABA(A)R)-mediated inhibitory postsynaptic currents. Most neurons showing this augmentation were identified as dopaminergic. In addition, in both stressed and unstressed animals, DOR activation decreases GABA(A)R currents in some VTA neurons. Surprisingly, both augmentation and inhibition were also observed when we bypassed the presynaptic terminal by iontophoretically applying GABA, indicating that postsynaptic mechanisms are responsible for both effects. Using a variety of blockers we determined that the augmentation is probably due to insertion of GABA(A)Rs into the synapse by a mechanism that is G-protein independent and mediated by activation of Akt via PI3K. GABA(A)Rs are inserted into the extra-synaptic plasma membrane before trafficking to the synapse, a mechanism consistent with our observation that the DOR-mediated increase in GABA(A)R signalling occurs significantly earlier in iontophoretically applied than in electrically evoked synaptic GABA. This G-protein-independent signalling pathway is not only a novel mechanism of opioid receptor-mediated inhibition, but it also represents the first reported link between activation of a GPCR and insertion of GABA(A)Rs into the plasma membrane.

Interaction between family history of alcoholism and Locus of Control in the opioid regulation of impulsive responding under the influence of alcohol.

BACKGROUND: Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX's behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX's behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX (Mitchell et al., 2007, Neuropsychopharmacology 32:439-449). Here, we tested whether this predictive relationship remains in the context of moderate alcohol intake. METHODS: In this study, we tested the effect of acute NTX (50 mg) on impulsive choice, motor inhibition, and attentional bias after ingestion of moderate ethanol (∼0.3 g/kg, n = 30 subjects). Subjects included those recruited from a pool of ∼1,200 UC Berkeley undergraduates on the basis of scores on the Barratt Impulsiveness Scale (BIS). RESULTS: Impulsive choice was positively correlated with breath alcohol concentration in placebo sessions. Locus of Control was again the sole predictor of NTX's effect on decision making among subjects with a family history of alcoholism. We also found a weak interaction between BIS scores and NTX's effect on impulsive choice. CONCLUSIONS: Our results reinforce the predictive relationship between Locus of Control and NTX's effect on decision making in those with a family history of alcoholism, suggesting a possible biological basis to this relationship.

Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.

Isolating event-related neuronal responses by deconvolution.

Although many studies in neuroscience are based on comparing neuronal responses to single, isolated sensory or motor events, multiple events frequently occur in close temporal proximity in freely moving animals. This often obscures the precise temporal correlation between each event and the relevant brain activity. By simulating neuronal responses in multi-event tasks, we show that perievent time histograms (PETHs) greatly distort the underlying true responses. We propose a multi-event deconvolution method that can separate the contribution of each event to the overall neuronal activity. The improvements over PETH in analyzing real data are demonstrated using simulated data and a sample electrophysiological recording obtained from rats in a task involving responses to a reward predictive cue.