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.

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.

Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

A Midbrain Circuit that Mediates Headache Aversiveness in Rats.

Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness.

Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor.

The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Ψ augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling.

Cortico-Accumbens Regulation of Approach-Avoidance Behavior Is Modified by Experience and Chronic Pain.

Although optimizing decisions between drives to avoid pain and to obtain reward are critical for survival, understanding the neuronal circuit activity that regulates choice during approach-avoidance conflicts is limited. Here, we recorded neuronal activity in the infralimbic (IL) cortex and nucleus accumbens (NAc) during an approach-avoidance task. In this task, disruption of approach by a pain-predictive cue (PPC-avoidance) is extinguished by experience and reinstated in a model of chronic pain. In the IL-NAc circuit, the activity of distinct subpopulations of neurons predicts the extent of PPC-avoidance observed. Furthermore, chemogenetic and optogenetic manipulations establish that IL-NAc circuitry regulates PPC-avoidance behavior. Our results indicate that IL-NAc circuitry is engaged during approach-avoidance conflicts, and modifications of this circuit by experience and chronic pain determine whether approach or avoidance occurs.

Mu Opioid Receptor Actions in the Lateral Habenula.

Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording. We found that the MOR selective agonist DAMGO inhibits a subset of LHb neurons both directly and by inhibiting glutamate release onto these cells. Paradoxically, DAMGO also presynaptically inhibited GABA release onto most LHb neurons. The behavioral effect of MOR activation will thus depend upon both the level of intrinsic neuronal activity in the LHb and the balance of activity in glutamate and GABA inputs to different LHb neuronal populations.

Ventral Pallidum Neurons Encode Incentive Value and Promote Cue-Elicited Instrumental Actions.

The ventral pallidum (VP) is posited to contribute to reward seeking by conveying upstream signals from the nucleus accumbens (NAc). Yet, very little is known about how VP neuron responses contribute to behavioral responses to incentive cues. Here, we recorded activity of VP neurons in a cue-driven reward-seeking task previously shown to require neural activity in the NAc. We find that VP neurons encode both learned cue value and subsequent reward seeking and that activity in VP neurons is required for robust cue-elicited reward seeking. Surprisingly, the onset of VP neuron responses occurs at a shorter latency than cue-elicited responses in NAc neurons. This suggests that this VP encoding is not a passive response to signals generated in the NAc and that VP neurons integrate sensory and motivation-related information received directly from other mesocorticolimbic inputs.

Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement.

Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement.

Alterations in the rostral ventromedial medulla after the selective ablation of µ-opioid receptor expressing neurons.

The rostral ventromedial medulla (RVM) exerts both inhibitory and excitatory controls over nociceptive neurons in the spinal cord and medullary dorsal horn. Selective ablation of mu-opioid receptor (MOR)-expressing neurons in the RVM using saporin conjugated to the MOR agonist dermorphin-saporin (derm-sap) attenuates stress and injury-induced behavioral hypersensitivity, yet the effect of RVM derm-sap on the functional integrity of the descending inhibitory system and the properties of RVM neurons remain unknown. Three classes of RVM neurons (on-cells, off-cells, and neutral cells) have been described with distinct responses to noxious stimuli and MOR agonists. Using single unit recording in lightly anesthetized rats, RVM neurons were characterized after microinjections of derm-sap or saporin. Derm-sap treatment resulted in a reduction in on-cells and off-cells when compared to saporin controls (P < 0.05). The number of neutral cells remained unchanged. After derm-sap treatment, RVM microinjections of the glutamate receptor agonist homocysteic acid increased tail-flick latencies, whereas the MOR agonist DAMGO had no effect. Furthermore, electrical stimulation of the periaqueductal gray produced analgesia in both derm-sap and saporin controls with similar thresholds. Microinjection of kynurenic acid, a glutamate receptor antagonist, into the RVM disrupted periaqueductal gray stimulation-produced analgesia in both saporin-treated and derm-sap-treated rats. These results indicate that MOR-expressing neurons in the RVM are not required for analgesia produced by either direct or indirect activation of neurons in the RVM.

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.

Understanding opioid reward.

Opioids are the most potent analgesics in clinical use; however, their powerful rewarding properties can lead to addiction. The scientific challenge is to retain analgesic potency while limiting the development of tolerance, dependence, and addiction. Both rewarding and analgesic actions of opioids depend upon actions at the mu opioid (MOP) receptor. Systemic opioid reward requires MOP receptor function in the midbrain ventral tegmental area (VTA) which contains dopaminergic neurons. VTA dopaminergic neurons are implicated in various aspects of reward including reward prediction error, working memory, and incentive salience. It is now clear that subsets of VTA neurons have different pharmacological properties and participate in separate circuits. The degree to which MOP receptor agonists act on different VTA circuits depends upon the behavioral state of the animal, which can be altered by manipulations such as food deprivation or prior exposure to MOP receptor agonists.

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.

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.

Catechol-O-methyltransferase genotype modulates opioid release in decision circuitry.

Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [¹¹C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.