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Acutely, pain is protective. It promotes escape from, and future avoidance of, noxious stimuli through strong and often lifetime associative memories. However, with persistent acute pain or when pain becomes chronic, these memories can promote negative emotions and poor decisions often associated with deleterious behaviors. In this review, we discuss how preclinical studies can provide insights into the relationship between cognition and chronic pain. We also discuss the concept of pain as a cognitive disorder and new strategies for treating chronic pain that emphasize inhibiting the formation of pain memories or promoting “forgetting” of established pain memories.

Diffuse noxious inhibitory controls (DNICs) is a pain-inhibits-pain phenomenon demonstrated in humans and animals. Diffuse noxious inhibitory control is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. Little is known as to why DNIC is dysfunctional in neuropathic pain. Here, we evaluated DNIC in the rat L5/L6 spinal nerve ligation (SNL) model of chronic pain using both behavioral and electrophysiological outcomes. For behavior, nociceptive thresholds were determined using response to noxious paw pressure on both hind paws as the test stimulus before, and after, injection of a conditioning stimulus of capsaicin into the left forepaw. Functionally, the spike firing of spinal wide-dynamic-range neuronal activity was evaluated before and during noxious ear pinch, while stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (ie, injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (ie, uninjured) paw. Systemic application of nor-binaltorphimine, a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-binaltorphimine into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the right central amygdala to promote diminished DNIC after neuropathy.

Chronic pain is highly comorbid with affective disorders, including major depressive disorder. A core feature of major depressive disorder is a loss of interest in previously rewarding activities. Major depressive disorder is also associated with negative affective biases where cognitive processes are modulated by the affective state. Previous work from our laboratory has shown that reward-related learning and memory is impaired in rodent models of depression generated through a variety of different manipulations. This study investigated different aspects of reward-related behaviour in a rodent model of chronic pain, the partial saphenous nerve injury (PSNI). Using our reward-learning assay, an impairment in reward learning was observed with no difference in sucrose preference, consistent with a lack of effect on reward sensitivity and similar to the effects seen in depression models. In a successive negative contrast task, chronic pain was not associated with changes in motivation for reward either under normal conditions or when reward was devalued although both sham and PSNI groups exhibited the expected negative contrast effect. In the affective bias test, PSNI rats developed a positive affective bias when treated with gabapentin, an effect not seen in the controls suggesting an association with the antinociceptive effects of the drug inducing a relatively more positive affective state. Together, these data suggest that there are changes in reward-related cognition in this chronic pain model consistent with previous findings in rodent models of depression. The effects seen with gabapentin suggest that pain-associated negative affective state may be remediated by this atypical analgesic.

Diseases and disorders such as Parkinson disease, schizophrenia, and chronic pain are characterized by altered mesolimbic dopaminergic neurotransmission. Dopamine release in the nucleus accumbens influences behavior through both tonic and phasic signaling. Tonic dopamine levels are hypothesized to inversely regulate phasic signals through dopamine D2 receptor feedback inhibition. We tested this hypothesis directly in the context of ongoing pain. Tonic and phasic dopamine signals were measured using fast-scan controlled-adsorption voltammetry and fast-scan cyclic voltammetry, respectively, in the nucleus accumbens shell of male rats with standardized levels of anesthesia. Application of capsaicin to the cornea produced a transient decrease in tonic dopamine levels. During the pain-induced hypodopaminergic state, electrically evoked phasic dopamine release was significantly increased when compared to baseline, evoked phasic release. A second application of capsaicin to the same eye had a lessened effect on tonic dopamine suggesting desensitization of TRPV1 channels in that eye. Capsaicin treatment in the alternate cornea, however, again produced coincident decreased dopaminergic tone and increased phasic dopamine release. These findings occurred independently of stimulus lateralization relative to the hemisphere of dopamine measurement. Our data show that (1) the mesolimbic dopamine circuit reliably encodes acute noxious stimuli; (2) ongoing pain produces decreases in dopaminergic tone; and (3) pain-induced decreases in tonic dopamine correspond to augmented evoked phasic dopamine release. Enhanced phasic dopamine neurotransmission resulting from salient stimuli may contribute to increased impulsivity and cognitive deficits often observed in conditions associated with decreased dopaminergic tone, including Parkinson disease and chronic pain.

Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.

Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.