Pain is fundamentally unpleasant, a feature that protects the organism by promoting motivation and learning. Relief of aversive states, including pain, is rewarding. The aversiveness of pain, as well ...as the reward from relief of pain, is encoded by brain reward/motivational mesocorticolimbic circuitry. In this Review, we describe current knowledge of the impact of acute and chronic pain on reward/motivation circuits gained from preclinical models and from human neuroimaging. We highlight emerging clinical evidence suggesting that anatomical and functional changes in these circuits contribute to the transition from acute to chronic pain. We propose that assessing activity in these conserved circuits can offer new outcome measures for preclinical evaluation of analgesic efficacy to improve translation and speed drug discovery. We further suggest that targeting reward/motivation circuits may provide a path for normalizing the consequences of chronic pain to the brain, surpassing symptomatic management to promote recovery from chronic pain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The experience of pain depends on interpretation of context and past experience that guide the choice of an immediate behavioral response and influence future decisions of actions to avoid harm. The ...aversive qualities of pain underlie its physiological role in learning and motivation. In this review, we highlight findings from human and animal investigations that suggest that both pain, and the relief of pain, are complex emotions that are comprised of feelings and their motivational consequences. Relief of aversive states, including pain, is rewarding. How relief of pain aversiveness occurs is not well understood. Termination of aversive states can directly provide relief as well as reinforce behaviors that result in avoidance of pain. Emerging preclinical data also suggests that relief may elicit a positive hedonic value that results from activation of neural cortical and mesolimbic brain circuits that may also motivate behavior. Brain circuits mediating the reward of pain relief, as well as relief-induced motivation are significantly impacted as pain becomes chronic. In chronic pain states, the negative motivational value of nociception may be increased while the value of the reward of pain relief may decrease. As a consequence, the impact of pain on these ancient, and conserved brain limbic circuits suggest a path forward for discovery of new pain therapies.
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GEOZS, IJS, IMTLJ, KILJ, OILJ, SBCE, SBJE, UL, UPUK
Mechanisms of craniofacial pain Chichorro, Juliana Geremias; Porreca, Frank; Sessle, Barry
Cephalalgia,
06/2017, Volume:
37, Issue:
7
Book Review, Journal Article
Peer reviewed
Aim
To provide an overview of mechanisms underlying craniofacial pain; to highlight peripheral and central adaptations that may promote chronification of pain in craniofacial pain states such as ...migraine and temporomandibular disorders (TMD).
Background
Pain is a common symptom associated with disorders involving craniofacial tissues including the teeth and their supporting structures, the temporomandibular joint and the muscles of the head. Most acute painful craniofacial conditions are easily recognized and well managed, but others, especially those that are chronic (e.g., migraine, TMD and trigeminal neuropathies), present clinical challenges. Preclinical studies have provided substantial information about the anatomical and physiological mechanisms related to the initiation and modulation of nociceptive signals in the trigeminal system. While knowledge of the mechanisms underlying chronic craniofacial pain remains limited, both clinical and preclinical investigations suggest that changes in afferent inputs to the brain as well as in brain structure and modulatory pathways occur in chronic pain. Collectively, these changes result in amplification of nociception that promotes and sustains craniofacial chronic pain states.
Conclusions
The increased understanding gained of the physiological and pathological processing of nociception in the trigeminal system has provided new perspectives for the mechanistic understanding of acute craniofacial pain conditions and the peripheral and central adaptations that are related to pain chronification. Such knowledge may contribute to improvements in currently available treatments as well as to the development of novel analgesic therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brain Circuits Encoding Reward from Pain Relief Navratilova, Edita; Atcherley, Christopher W; Porreca, Frank
Trends in neurosciences (Regular ed.),
11/2015, Volume:
38, Issue:
11
Journal Article
Peer reviewed
Open access
Relief from pain in humans is rewarding and pleasurable. Primary rewards, or reward-predictive cues, are encoded in brain reward/motivational circuits. While considerable advances have been made in ...our understanding of reward circuits underlying positive reinforcement, less is known about the circuits underlying the hedonic and reinforcing actions of pain relief. We review findings from electrophysiological, neuroimaging, and behavioral studies supporting the concept that the rewarding effect of pain relief requires opioid signaling in the anterior cingulate cortex (ACC), activation of midbrain dopamine neurons, and the release of dopamine in the nucleus accumbens (NAc). Understanding of circuits that govern the reward of pain relief may allow the discovery of more effective and satisfying therapies for patients with acute or chronic pain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. ...The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in people with comorbid depression, anxiety, and other chronic pain conditions. Treatment of medication overuse headache has three components. First, patients need education and counselling to reduce the intake of medication for acute headache attacks. Second, some patients benefit from drug withdrawal (discontinuation of the overused medication). Finally, preventive drug therapy and non-medical prevention might be necessary in patients at onset of treatment or in patients who do not respond to the first two steps. The optimal therapeutic approach requires validation in controlled trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pain is a manifestation of rheumatoid arthritis (RA) that is mediated by inflammatory and non-inflammatory mechanisms and negatively affects quality of life. Recent findings from a Phase 3 clinical ...trial showed that patients with RA who were treated with a Janus kinase 1 (Jak1) and Janus kinase 2 (Jak2) inhibitor achieved significantly greater improvements in pain than those treated with a tumor necrosis factor blocker; both treatments resulted in similar changes in standard clinical measures and markers of inflammation. These findings suggest that Jak1 and Jak2 inhibition may relieve pain in RA caused by inflammatory and non-inflammatory mechanisms and are consistent with the overarching involvement of the Jak-signal transducer and activator of transcription (Jak/STAT) pathway in mediating the action, expression, and regulation of a multitude of pro- and anti-inflammatory cytokines. In this review, we provide an overview of pain in RA, the underlying importance of cytokines regulated directly or indirectly by the Jak/STAT pathway, and therapeutic targeting of the Jak/STAT pathway in RA. As highlighted herein, multiple cytokines directly or indirectly regulated by the Jak/STAT pathway play important roles in mediating various mechanisms underlying pain in RA. Having a better understanding of these mechanisms may help clinicians make treatment decisions that optimize the control of inflammation and pain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ...ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A Nafion and poly(3,4-ethylenedioxythiophene) (PEDOT) containing composite polymer has been electropolymerized on carbon-fiber microelectrodes with the goal of creating a mechanically stable, ...robust, and controllable electrode coating that increases the selectivity and sensitivity of in vivo electrochemical measurements. The coating is deposited on carbon-fiber microelectrodes by applying a triangle waveform from +1.5 V to −0.8 V and back in a dilute solution of ethylenedioxythiophene (EDOT) and Nafion in acetonitrile. Scanning electron microscopy demonstrated that the coating is uniform and ∼100 nm thick. Energy-dispersive X-ray spectroscopy demonstrated that both sulfur and fluorine are present in the coating, indicating the incorporation of PEDOT (poly(3,4-ethylenedioxythiophene) and Nafion. Two types of PEDOT:Nafion coated electrodes were then analyzed electrochemically. PEDOT:Nafion-coated electrodes made using 200 μM EDOT exhibit a 10–90 response time of 0.46 ± 0.09 s versus 0.45 ± 0.11 s for an uncoated fiber in response to a 1.0 μM bolus of dopamine. The electrodes coated using a higher EDOT concentration (400 μM) are slower with a 10–90 response time of 0.84 ± 0.19 s, but display increased sensitivity to dopamine, at 46 ± 13 nA/μM, compared to 26 ± 6 nA/μM for the electrodes coated in 200 μM EDOT and 13 ± 2 nA/μM for an uncoated fiber. PEDOT:Nafion-coated electrodes were lowered into the nucleus accumbens of a rat, and both spontaneous and electrically evoked dopamine release were measured. In addition to improvements in sensitivity and selectivity, the coating dramatically reduces acute in vivo biofouling.
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IJS, KILJ, NUK, PNG, UL, UM
The amygdala is a key subcortical region believed to contribute to emotional components of pain. As opioid receptors are found in both the central (CeA) and basolateral (BLA) nuclei of the amygdala, ...we investigated the effects of morphine microinjection on evoked pain responses, pain-motivated behaviors, dopamine release in the nucleus accumbens (NAc), and descending modulation in rats with left-side spinal nerve ligation (SNL). Morphine administered into the right or left CeA had no effect on nerve injury-induced tactile allodynia or mechanical hyperalgesia. Right, but not left, CeA morphine produced conditioned place preference (CPP) and increased extracellular dopamine in the NAc selectively in SNL rats, suggesting relief of aversive qualities of ongoing pain. In SNL rats, CPP and NAc dopamine release following right CeA morphine was abolished by blocking mu opioid receptor signaling in the rostral anterior cingulate cortex (rACC). Right CeA morphine also significantly restored SNL-induced loss of the diffuse noxious inhibitory controls, a spino-bulbo-spinal pain modulatory mechanism, termed conditioned pain modulation in humans. Microinjection of morphine into the BLA had no effects on evoked behaviors and did not produce CPP in nerve-injured rats. These findings demonstrate that the amygdalar action of morphine is specific to the right CeA contralateral to the side of injury and results in enhancement of net descending inhibition. In addition, engagement of mu opioid receptors in the right CeA modulates affective qualities of ongoing pain through endogenous opioid neurotransmission within the rACC, revealing opioid-dependent functional connections from the CeA to the rACC.
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.