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

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.

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations.

Spinal cord stimulation (SCS) is an interventional nonpharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). Although randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, nonspecific effects of treatment variables (eg, paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations.

The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females.

Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.