psychology

Reward, motivation and emotion of pain and its relief

Frank Porreca* and Edita Navratilova Department of Pharmacology, University of Arizona, Tucson, AZ 84724 and Collaborative Research, Mayo Clinic, Scottsdale, AZ, 85054

Abstract

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.

Keywords

chronic pain; mesolimbic dopamine circuit; nucleus accumbens; opioid signaling; cingulate cortex; hedonic response

Introduction: Qualities of pain and pain relief

Although pain is familiar to almost everyone, its precise definition continues to be elusive.

Pain is most often viewed in the realm of somatosensation. However, this conceptualization

is problematic as unlike most other sensations that are usually affectively neutral, pain has

the additional quality of aversiveness. To focus only on aversive qualities is also problematic

as there are many aversive conditions that are clearly recognized by humans as something

other than pain. Fields has described the unique features of pain aversiveness as a quality of

"algosity" [30]. The qualities that make pain unique, and immediately recognizable to

humans, have been discussed since antiquity. Aristotle proclaimed the doctrine of the five

*Corresponding author: Frank Porreca, Ph.D., Department of Pharmacology, University of Arizona, Tucson, AZ 85724, (520) 626-7421 (voice), (520) 626-4182 (fax), [email protected].

Conflict of Interest: The authors have no conflicts of interest to declare.

HHS Public Access Author manuscript Pain. Author manuscript; available in PMC 2018 April 01.

Published in final edited form as: Pain. 2017 April ; 158(Suppl 1): S43–S49. doi:10.1097/j.pain.0000000000000798.

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senses (sight, hearing, smell, taste and touch) but did not include pain [23]. For the ancient

Greek philosophers, pain was included with pleasure as "passions of the soul". While not

technical, this definition was nevertheless elegant and meaningful. The recognition of pain

and pleasure as opposites on a hedonic spectrum revealed an understanding that these two

emotions provide motivations that guide our decisions for action selection, shaping the lives

of organisms.

Pain is a call to action. Like hunger, thirst and desire for sleep, pain is a part of the body’s

survival systems that collectively are responsible for protecting the organism [25]. These

primordial emotions, including pain, are characterized by a specific sensation that signals

deviation from homeostasis and an intention to satisfy the need for homeostatic balance [22].

The sensation of pain generates an aversive state that demands a behavioral response (for

pain, a motivation to seek relief). In contrast, relief of pain, and return to homeostatic

balance is rewarding (see below). Because primordial emotions often signal that the very

existence of the organism is threatened, they are ancient and encoded by phylogenetically

conserved neural circuits consisting of afferent sensory pathways and areas of the brain

including the thalamus, insula and cingulate cortex. These cortical regions have connections

with the valuation/decision mesolimbic circuit, which integrates the information from

multiple competing emotions and selects the behavioral action that offers the greatest benefit

to the organism. The mesolimbic system also serves in learning the situations that lead to

deviation or restoration of homeostasis and thus helps the organism to avoid aversive

situations and find rewards.

Melzack and Casey first proposed the multidimensional model of pain in 1968 [55]. An

important concept that emerged from this model was the partial separation of the affective

and motivational features of pain from its sensory and discriminative qualities. Separation of

these features also implied different anatomical substrates which were suggested to involve

medial and lateral ascending pathways for affective/motivational and sensory/discriminative

features, respectively [86]. Viewing pain as a human experience that involved the synthesis

of sensory, affective and cognitive dimensions represented a momentous shift from

unidimensional sensory models and underscored the distinction between pain and

nociception and the lack of consistent relationship between pain and the state of the tissues.

These concepts were based on clinical observation including, for example, the early studies

by Beecher that soldiers in battle with serious wounds did not report feeling pain [11]. Such

findings were explained, in part, by the gate control theory of pain proposed by Melzack and

Wall in 1965 [54]. Melzack wrote that neural signals never enter the nervous system as a

blank canvass. Rather, nociceptive signals are always subject to interpretation of meaning

based on the present context and of past experience (i.e., learning and memories) [53]. Fields

and colleagues have subsequently characterized descending bidirectional pain modulatory

circuits that can enhance or diminish pain based on multiple factors including context, stress,

expectation, and others ([31] for review). The role of these descending circuits in

circumstances of competing motivations such as reward and threat have led to the the

formulation of the motivational-decision model of pain [32] (see below).

While the deconstruction of pain into multiple dimensions has been extraordinarily useful,

the human experience of pain appears to require synthesis of all of these components

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including affective, sensory and cognitive dimensions. Ploner and colleagues reported a

patient with a stroke-induced lesion in the somatosensory cortex who could not identify the

source of a nociceptive stimulus on the contralateral side but found it unpleasant [70].

However, the patient refused to identify the unpleasant nature of the stimulus as "pain",

supporting both the partial dissociation between sensory and affective qualities of pain and

the need to integrate these qualities to form the human experience. Fields has elegantly noted

that while the affective dimension of pain is partially separable from its "sensory" qualities,

pain affect is nevertheless tightly related to the degree of nociceptive inputs and can

therefore be appropriately termed "sensory" as well. Evidence of partial dissociation of

affective and sensory features of pain also emerge from cingulotomy studies where "pain"

continues to be perceived but is considered no longer bothersome [18; 100; 101], as well as

from imaging studies where pain unpleasantness can be modulated independently of sensory

intensity, or where pain can be imagined [72]. Opiates are one of the most important classes

of drugs to treat pain and produce their effects preferentially on modulation of affective,

rather than sensory, dimensions of pain [65]. Navratilova and colleagues demonstrated that

activation of cortical opioid receptors could selectively modulate pain aversiveness without

influencing evoked reflexive measures in a preclinical model of chronic pain (52). This

finding suggested the existence of distinct central mechanisms mediating affective qualities

of pain. The aversive aspects of pain are the main complaint of patients. The unpleasant

qualities of pain are essential in its physiological role to increase survival by promoting

learning and influencing future decisions to avoid harm.

The neural mechanisms of appetitive learning have received considerable attention but our

understanding of aversive learning remains limited. At present, very little is known about the

mechanisms and neural circuitry that mediate aversiveness of pain. Neurons in the

mesolimbic reward valuation network projecting from the ventral tegmental area to the

nucleus accumbens have been implicated in both appetitive and aversive learning [17]. Thus,

an unexpected reward increases phasic dopamine release while omission of an expected

reward reduces phasic dopamine [75]. The difference between an expected and an actual

outcome generates a prediction error that underlies reinforcement learning [84]. Roy and

colleagues have elegantly described mechanisms by which responses of the brain to

nociceptive inputs are influenced by learning using fMRI signals related to prediction errors

[74]. They found that pain prediction errors were encoded in the periaqueductal gray (PAG),

a part of the brain that is integral not only in ascending nociceptive signals but in descending

pain modulation. The expected value-related input to the PAG arose from the ventromedial

prefrontal cortex with relay of prediction error signals to prefrontal cortical regions that

drive behavioral actions including orbitofrontal, anterior mid-cingulate and dorsomedial

prefrontal cortices. Investigation of the affective qualities of pain and aversive learning using

pre-clinical models that allow detailed investigation of the mediating circuits is in its earliest

stages.

The human experience of pain is also influenced by other motivational, emotional and

cognitive states ranging from basic physiological needs such as hunger or response to

immediate threat to human rational thinking. Expectation of pain, or of pain relief, has been

shown to dramatically alter not only the degree and quality of pain that is experienced, but

also to increase or decrease the efficacy of even the most powerful opioids [15].

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Psychological manipulations of attention and distraction also alter pain, as does the

emotional state, and even the religious beliefs of the subject [49; 88; 97]. Modulation of

mood with pleasant and unpleasant odors has been demonstrated to positively or negatively

influence emotional states resulting in reduced or increased pain [88]. Neuroimaging studies

have found that these modulatory effects on pain are also reflected in altered activity in

higher order pain related brain circuits [reviewed in 19; 35].

Assessment of ongoing pain in rodents

Mogil has suggested that a preclinical pain model is comprised of three basic components:

the subjects, the assay, and the outcome measure [56]. Each component requires careful

consideration in order to optimize potential translational value to the proposed human pain

syndrome being modeled. Most preclinical studies of pain have emphasized output measures

that rely on responses to evoked stimuli [56; 87]. While such stimuli engage the nociceptive

pathway and are thought to accurately reflect nociceptive pain mechanisms, these reflexive

responses do not capture the biologically relevant aversive qualities of pain. Reflexive

behaviors can often be observed in decerebrated animals [98] and do not require learning

[87], an essential feature of physiological pain. While the affective (unpleasant) quality of an

evoked pain stimulus is essential in eliciting the reflexive withdrawal response, the response

threshold has not easily allow mechanistic evaluation of affective qualities. Multiple

approaches have and are being advanced to expand outcome measures that would better

capture the affective (unpleasant) quality including, for example, place escape avoidance

paradigms, ultrasonic vocalization, pain-suppressed behaviors and facial responsivity scales

(see [40] for review). Efforts in this domain are often intended to assess pain without the

need for an evoked reflexive withdrawal response. Most importantly, a lowered response

threshold for an acutely applied stimulus can occur in the absence of ongoing pain. This can

be seen, for example, in lightly sunburned skin in which a normally innocuous heat stimulus

is felt as burning pain [16; 69]. Most clinically relevant pains have a tonic component that is

not revealed by most currently used methods for pain assessment.

The presence of ongoing pain in animals without need for an evoked stimulus from the

experimenter has been demonstrated using the conditioned place preference (CPP) learning

paradigm that is based on the affective and motivational qualities of pain [41]. Because

ongoing pain provides an ongoing motivational drive to seek relief, preference for a context associated with relief of pain can be utilized as a measure of pain aversiveness [60].

Treatments that are clinically effective against ongoing pain in humans are effective in the

CPP paradigm and the reverse is also true [41; 60; 61] providing support for this approach.

CPP to pain relief was also demonstrated following axotomy of the sciatic nerve to elicit

complete denervation of the hindpaw [26; 27] confirming the presence of an aversive state

that likely reflects "spontaneous" neuropathic pain in this assay [71] and providing an

important control that eliminated concerns of pain resulting from tactile stimulation during

ambulation within the testing apparatus [71].

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Relief of ongoing pain is rewarding

PET imaging studies have shown that placebo analgesia is associated with release of

dopamine in brain areas associated with reward [77]. Human imaging has demonstrated that

offset of an acute pain stimulus produces a positive BOLD signal in the nucleus accumbens,

an area associated with reward-aversion processing in humans [8]. Navratilova and

colleagues investigated whether pain relief produced direct activation of reward pathways

using a preclinical model of post-operative pain (i.e., incisional injury of the hindpaw) in rats

[61]. Following hindpaw incision, a context was paired with a peripheral nerve block and

preference was assessed at multiple time points, exploiting the time-dependent nature of

post-operative pain. Following surgery, humans demonstrate a period of strong ongoing pain

that transitions to a longer-lasting state of tenderness in the injured area (i.e., hyperalgesia)

[57]. Likewise, this model of incisional pain was shown to produce time-related ongoing

pain [61]. Thus, CPP to peripheral nerve block was demonstrated one day but not four days

after incisional injury. Only animals with injury demonstrated CPP suggesting that the relief

of the aversive state induced by ongoing post-surgical pain is rewarding, consistent with the

lack of intrinsic reward value of lidocaine.

The observed CPP following peripheral nerve block was also consistent with increased Fos

expression in dopaminergic neurons in the ventral tegmental area and elevated tonic levels of

dopamine in the nucleus accumbens detected one day but not four days after injury.

Critically, the CPP resulting from peripheral nerve block was prevented by inactivation of

the ventral tegmental area as well as blockade of dopaminergic receptors in the nucleus

accumbens. The findings from relief of incisional pain with peripheral nerve block were

extended to demonstrate the effectiveness of relief of ongoing pain with non-opioid

treatments across multiple experimental pain conditions (i.e., nociceptive, inflammatory,

neuropathic and cancer pain) (see [60] for review). For example, in an animal model of

migraine-related pain resulting from application of inflammatory mediators to the dura

mater of rats, anti-migraine drugs induced CPP as well as increased dopamine release in the

nucleus accumbens shell [24]. Collectively, these studies demonstrated that activation of

dopaminergic neurons in the ventral tegmental area and release of dopamine and activation

of dopaminergic receptors in the nucleus accumbens mediates the reinforcing effect of pain

relief. Importantly, CPP and nucleus accumbens dopamine release was demonstrated

selectively in injured animals following pain relieving treatments that did not have intrinsic

reward value in uninjured animals [60]. These findings were consistent with other studies

suggesting that activation of the mesolimbic motivation/reward circuit contributes to both

pain perception and pain relief. In a BOLD imaging study performed with healthy

volunteers, the activity of the nucleus accumbens was decreased during onset of noxious

thermal stimuli and was increased during offset of stimuli [6; 8]. Nucleus accumbens

activity was also correlated with relief pleasantness associated with a cue signaling safety

from pain [46].

Mechanisms of pain relief

Opioids are currently our most effective and widely used drugs for the treatment of

moderate-to-severe pain. Multiple studies have demonstrated that opioid drugs have a

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preferential effect on the affective qualities of pain. Consistent with their clinical efficacy,

the anterior cingulate cortex (ACC) expresses high levels of opioid receptors in humans, as

well as in rats [91]. PET imaging studies in humans have demonstrated the release of

endogenous opioids in this cortical area during experimentally-induced pain as well as

during placebo analgesia [77; 92]. A positive correlation between pain-induced endogenous

opioid release in the ACC and reduced pain affect has been demonstrated [103]. Thus,

release of endogenous opioids in the ACC is implicated both with pain and with pain relief.

These human investigations suggested that the relief of pain aversiveness may ultimately be

mediated by opioid signaling in the rostral ACC and subsequent activation of dopamine

neurotransmission in the nucleus accumbens.

The ACC has previously been implicated in encoding the aversive features of pain [90].

Bushnell and colleagues used imaging techniques to demonstrate that the ACC, but not

somatosensory cortex, is activated when unpleasantness of pain is increased with hypnotic

suggestion [73]. In contrast, increasing sensory intensity of a noxious stimulus increased

activity in both the somatosensory and anterior cingulate cortex, supporting the partial

separation of affective and sensory features of pain. Johansen and colleagues used a

conditioned place avoidance paradigm to demonstrate that lesion of the rostral anterior

cingulate cortex (rACC) disrupted the aversive aspects of hindpaw formalin injection in rats

without affecting evoked responses [38; 39]. Lesion of the rACC was similarly demonstrated

to abolish CPP to pain relieving treatments in rats with spinal nerve ligation injury, without

altering evoked responses [71]. These studies support the alteration of motivation from

modulation of pain-induced aversiveness [71].

Consistent with the partial separation of affective and sensory features of pain, LaGraize et

al., have shown that administration of morphine into the ACC of rats with experimental

neuropathic pain, selectively decreases the affective/motivational measures of pain with no

alteration of mechanical paw withdrawal threshold [42]. Similarly, ACC morphine treatment

was sufficient to produce CPP and to elicit release of dopamine in the NAc only in injured

rats [62]. The MOR in the ACC may thus represent a key target for relief of pain

aversiveness. This conclusion is supported by the demonstration that the CPP, and NAc DA

release, observed in rats with neuropathic or incisional injuries was required for the pain

relieving effect of systemic morphine as well as non-opioid pain relieving treatments

including spinal clonidine (α2 adrenergic agonist), systemic gabapentin or peripheral nerve block [62]. These findings provide a neural basis for the rewarding effects of pain relief by

showing that they depend on opioidergic circuits in the ACC and downstream dopaminergic

signaling in the NAc. Thus, endogenous opioidergic circuits within the ACC appear to be

both necessary and sufficient for reward from pain relief. The role of endogenous opioid

activity in pain relief has also been demonstrated by imaging studies in healthy volunteers.

These investigations revealed positive correlation between brain activations in cortico-limbic

regions evoked by painful stimulation and reductions in subjective pain reports from

identical noxious stimulation during systemic opioid administration [95]. While this

conclusion has been supported by current experimental data, non-opioid mechanisms may

also be important. A recent study in humans of pain relief through mindfulness meditation

showed a lack of dependence on endogenous opioids [102]. Future studies will be required

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to determine the overall generality of opioid mechanisms as the major mediator of relief of

pain aversiveness.

Relief as an emotion

The affective quality of relief from aversive states, including pain, is not well understood.

Relief is a complex emotion that is difficult to associate with a clear affective valence.

Studies in humans have suggested that relief may reflect the experience of a negative valence

diminishing toward a neutral valence [33; 78]. Other studies, however, have suggested that

relief may also be associated with increasing positive valence [46]. Becerra and Borsook

reported that the offset of a noxious stimulus produced activation of the nucleus accumbens

in human subjects [8; 9]. This observation was consistent with the findings of Leknes and

colleagues who found that pain offset increases self-reported pleasantness and activates

brain reward areas [45; 80]. Indeed, the same group in a study in which moderate pain was

the best outcome compared to more intense pain, demonstrated a hedonic flip so that

moderate pain was considered pleasurable [44]. Studies by Franklin and colleagues suggest

that both decreased negative affect and increased positive affect may simultaneously

contribute the emotion of relief [34]. Data demonstrating the release of endogenous opioids

in the rACC with pain relief suggest that both positive and negative reinforcement learning

participates in the motivation to seek relief.

Competing motivations: the motivation decision model

As noted above, descending modulation of nociceptive signals from the periphery is

bidirectional based on interpretation of context, past experience, emotional and stress levels

and other factors [89]. The output of the brain in producing modulation of nociceptive

signals ultimately arises from the rostral ventromedial medulla (RVM) where OFF and ON

cells that respectively mediate descending inhibition and facilitation have been identified

[29]. The motivation-decision model of Fields has suggested a context dependent activation

of these cells that guide the behavioral outcome of a nociceptive stimulus [32]. Thus,

activation of nociceptors in a neutral setting elicits descending facilitation that focuses

attention on pain with behavioral outcomes of recovery and healing. In the presence of

competing motivations such as response to a threat or obtaining a food reward, conflict

requires a neural cost-benefit computation and making a decision that leads to the best

behavioral outcome for the organism. Thus, pain is suppressed when a more desirable

outcome is advantageous, e.g., escape from a dangerous situation or obtaining a desired

reward. By extension, the model also predicts that in situations when attending to pain is the

most advantageous goal, conflicting rewards may be suppressed. Rewards such as food,

pleasurable music or odors are known to suppress pain (see review in [47]). However, the

impact of ongoing pain on the value of rewards is less understood.

Chronic pain and impact on reward circuits

Recently, research from Berridge laboratory, and others, have described rewards as a

complex psychophysical construct composed of two main processes involving hedonic

pleasure (i.e., “liking”) and motivation (i.e., “wanting”) to obtain rewards [20]. Hedonic

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qualities are thought to be encoded primarily by the release of endogenous opioids in brain

regions including the orbitofrontal cortex, the anterior cingulate cortex, the amygdala and

the nucleus accumbens (NAc) while motivation to acquire rewards is mainly driven by

dopamine signaling in the mesolimbic circuit [12–14; 67]. These areas overlap with brain

circuits important for motivational and affective aspects of pain and pain relief [10; 47; 59],

providing neural evidence for the interaction between pain and reward.

Chronic pain changes the behavioral goals shifting the focus away from other motivations

toward achieving homeostatic equilibrium (i.e., relief). The tonic long-lasting motivational

shift could result in time-dependent adaptive changes in motivational circuits contributing to

pain chronification [2]. Consistent with this, brain neuroimaging studies in patients with

chronic conditions including back pain, neuropathic pain, fibromyalgia, irritable bowel

syndrome, headache, complex regional pain syndrome (CRPS) and osteoarthritis have

demonstrated functional, anatomical (structural) or molecular changes. For example,

widespread abnormalities were identified in grey matter density [37; 52], in the connectivity

of the white matter [37], as well as in glutamate, opioid and dopamine neurotransmission

(see [3; 85] for review).

Many of the brain changes observed in chronic pain patients involve regions encoding

affective, emotional and motivational contexts. Baliki and colleagues observed that at the

offset of an acute thermal stimulation, brain responses in the NAc differed between healthy

subjects and patients with chronic back pain [6]. In normal subjects, a positive phasic

nucleus accumbens signal at pain offset reflected prediction of reward associated with relief

of pain. In contrast, a negative NAc signal was found in patients, consistent with return of

attention to their ongoing chronic pain at the termination of acute stimulus. The magnitude

of nucleus accumbens activity at the stimulus offset positively correlated with the subject’s

ratings of ongoing back pain. These findings suggest that the motivational value of acute

pain offset may be distorted in chronic pain conditions.

Furthermore, Baliki and colleagues monitored fMRI responses in patients with back pain

over several years. These investigations identified that the strength of functional connectivity

between NAc and PFC predicted whether the patient will recover, or will transition to

chronic pain [7] and suggest that as pain becomes chronic, pain perception may shift from

sensory to emotional brain regions [6]. Interestingly, similar abnormalities in prefrontal and

mesolimbic regions were also observed in rats several months after experimental

neuropathic pain [79]. Such observations suggest that anatomical and functional changes in

reward/motivation and learning circuits may lead to the co-morbid emotional and cognitive

disorders often observed in chronic pain patients [4; 5].

Impact of chronic pain on motivational and hedonic components of reward

Despite the overwhelming evidence of overlapping neurocircuitry for pain and pleasure, and

documented abnormalities in these regions in chronic pain states, data demonstrating

hedonic or motivational deficits in chronic pain patients are scarce. Comprehensive

evaluations of the impact of chronic pain on reward deficits in humans are difficult and the

outcomes have been variable. For example, a study in patients with chronic low back pain

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(CLBP) did not find altered ratings of pleasure or aversion to sweet, salty, or bitter tastants

[82]. However, a different study in CLBP patients detected a small, but significant, decrease

in pleasure from high fat pudding, although no change was found in response to sweet

solutions [36]. In a recent questionnaire-based study, patients with chronic pain reported

reduced reward responsiveness [28]. Other investigations in patients with neuropathic pain

demonstrated diminished desire to participate in activities, suggesting possible deficits in

motivation, but contributions of pain-related decreased physical mobility could not be ruled

out [51; 63]. It should be pointed out, however, that these outcomes in patients may be

influenced for example by medications, thus direct causal link between pain and reward

deficits remains unclear.

Studies in rodent models of inflammatory or neuropathic pain show diminished rewards

from intracranial self-stimulation or from morphine [43; 64]. However, there are conflicting

reports on the effects of pain on natural food rewards, including sucrose preference, with

some studies demonstrating decreased sucrose consumption [1; 48; 50; 81; 93; 99] while

others show no change [66; 76; 94]. A study by Schwartz and colleagues used mice with

sciatic nerve injury-induced neuropathic pain or CFA-induced inflammation and

demonstrated that even though injured animals showed no deficits in sucrose preference,

they displayed decreased motivation for food reward in a progressive ratio operant

responding task [76]. Moreover, the authors showed that decreased motivation during

chronic pain required galanin-mediated synaptic modifications in the nucleus accumbens.

We used a facial reactivity score in rats to investigate the influence of chronic neuropathic

pain on hedonic responses to food rewards independently from motivation [66]. Sweet or

bitter liquid solutions were passively delivered via intraoral catheters to rats 21 days after

spinal nerve ligation or sham surgery and “liking/disliking” responses were scored according

to a facial reactivity scale. Neuropathic rats did not differ from sham controls in either

“liking” or “disliking” reactions, suggesting no differences in perceived hedonic value of

sweet or bitter tastants. The possibility that hedonic deficits could be detected by other

approaches, or would be observed at later time points following injury requires further study.

Possible motivational deficits during acute and chronic pain was investigated using fixed-

and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient

inflammatory or chronic neuropathic pain [66]. Assessment of response acquisition and

break points under the progressive ratio schedule revealed no differences between sham and

SNL rats for up to 120 days post-injury. However, rats with inflammation showed

decrements in lever pressing and break points on post-CFA days 1 and 2 that normalized by

day 4, consistent with transient ongoing pain. Thus, while acute, ongoing inflammatory pain

may transiently reduce reward motivation, influences of chronic neuropathic pain on hedonic

or motivational responses to food rewards could not be detected [66]. Whether, and how,

chronic pain may influence the value of other natural rewards remains to be determined.

However, these findings suggest that adaptations that allow normal reward responding to

food, regardless of chronic pain, may be of evolutionary benefit to promote survival.

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Pain in discovery research

Pain discovery research has largely focused on modulation of behavioral responses to

noxious stimuli through interventions aimed at modulation of transduction, transmission, or

central amplification of neural signals [68]. Pain relieving actions of blockade of nociceptive

input arising from the periphery is clinically validated (e.g., local anesthetics), however this

is not always possible in patients [96]. Additionally, inhibition of the physiological function

of pain can be dangerous and can lead to bodily harm as seen in patients with congenital

insensitivity to pain [21; 58]. Pain relief, however, can also be achieved by selective

modulation of pain affect (e.g., placebo, hypnotic suggestion, attention/distraction,

neurostimulation)[72; 83; 88]. Importantly, the demonstration that opioids preferentially act

in the brain to selectively modulate pain affect (52) suggests opportunities for novel

mechanisms to engage brain circuits for pain relief. Thus, relief of pain is often managed

clinically largely through modulation of pain affect.

Currently, the contribution of preclinical studies to the discovery of pain therapies focus

primarily on reduction of one dimension (intensity). This approach does not reflect how pain

is managed clinically or fit with current understanding of pain relief as a multidimensional

and emotional experience. Preclinical discovery strategies might be improved by including

assessments of affective/motivational aspects of pain at behavioral, and brain circuit levels.

As the motivational and emotional neural circuits engaged in relief are phylogenetically

ancient, and highly conserved across species, effective pain relief, regardless of the site and

the molecular target, must be reflected in opioid and dopamine activity in motivation/

aversion circuits. Activity analyses within these circuits may thus serve as a novel readout of

efficacy with high likelihood of translational relevance that could increase chances of

clinical success.

Conclusions

Knowledge of circuits that underlie pain affect remains rudimentary. However, it now

appears that pain, and pain relief, may be reflected by activation of opioidergic and

dopaminergic cortico-limbic circuits. Clinical impression suggests that the effectiveness of

pain relieving treatments may change in patients with increased chronicity of pain.

Consistent with this, neuroimaging studies provide evidence of anatomical and neurological

changes in these circuits in the setting of chronic pain in which there may be sustained

nociceptive drive for very long times, even decades. Maladaptive changes in reward and

valuation circuits could represent a "pain memory" so that motivational decisions are skewed

toward increasing the magnitude and cost of nociceptive inputs while diminishing the value

and benefit of pain relief. Increased mechanistic studies in preclinical models of the

intersection between pain, chronic pain and reward and motivation circuits may offer new

approaches for improvement of therapy.

Acknowledgments

This work was supported by R01DA034975 and by R01DA041809 from the NIH-NIDA. We thank Professor Howard Fields for helpful comments on the manuscript.

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