Nociceptive input after peripheral nerve injury results in cognitive impairment and alterations in primary afferent physiology in rats.

Pain alters cognitive performance through centrally mediated effects in the brain. In this study, we hypothesized that persistent activation of peripheral nociceptors after injury would lead to the development of a chronic pain state that impairs attention-related behavior and results in changes in peripheral neuron phenotypes. Attentional performance was measured in rats using the 5-choice serial reaction time titration variant to determine the initial impact of partial L5 spinal nerve ligation and the effect of persistent nociceptor activation on the resolution of injury. The changes in peripheral neuronal sensibilities and phenotypes were determined in sensory afferents using electrophysiologic signatures and receptive field properties from dorsal root ganglion recordings. Partial spinal nerve injury impaired attentional performance, and this was further impaired in a graded fashion by nociceptive input through an engineered surface. Impairment in attention persisted for only up to 4 days initially, followed by a second phase 7 to 10 weeks after injury in animals exposed to nociceptive input. In animals with prolonged impairment in behavior, the mechanonociceptors displayed a persistent hypersensitivity marked by decreased threshold, increased activity to a given stimulus, and spontaneous activity. Nerve injury disrupts attentional performance acutely and is worsened with peripheral mechanonociceptor activation. Acute impairment resolves, but persistent nociceptive activation produces re-emergence of impairment in the attention-related task associated with electrophysiological abnormalities in peripheral nociceptors. This is consistent with the development of a chronic pain state marked by cognitive impairment and related to persistently abnormal peripheral input.

Incisional Nociceptive Input Impairs Attention-related Behavior and Is Associated with Reduced Neuronal Activity in the Prefrontal Cortex in Rats.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Cognitive capacity may be reduced from inflammation, surgery, anesthesia, and pain. In this study, we hypothesized that incision-induced nociceptive input impairs attentional performance and alters neuronal activity in the prefrontal cortex. METHODS: Attentional performance was measured in rats by using the titration variant of the 5-choice serial reaction time to determine the effect of surgical incision and anesthesia in a visual attention task. Neuronal activity (single spike and local field potentials) was measured in the medial prefrontal cortex in animals during the task. RESULTS: Incision significantly impaired attention postoperatively (area under curve of median cue duration-time 97.2 ± 56.8 [n = 9] vs. anesthesia control 25.5 ± 14.5 s-days [n = 9], P = 0.002; effect size, η = 0.456). Morphine (1 mg/kg) reduced impairment after incision (area under curve of median cue duration-time 31.6 ± 36.7 [n = 11] vs. saline 110 ± 64.7 s-days [n = 10], P < 0.001; η = 0.378). Incision also decreased cell activity (n = 24; 1.48 ± 0.58 vs. control, 2.93 ± 2.02 bursts/min; P = 0.002; η = 0.098) and local field potentials (n = 28; η = 0.111) in the medial prefrontal cortex. CONCLUSIONS: These results show that acute postoperative nociceptive input from incision reduces attention-related task performance and decreases neuronal activity in the medial prefrontal cortex. Decreased neuronal activity suggests nociceptive input is more than just a distraction because neuronal activity increases during audiovisual distraction with similar behavioral impairment. This suggests that nociceptive input and the medial prefrontal cortex may contribute to attentional impairment and mild cognitive dysfunction postoperatively. In this regard, pain may affect postoperative recovery and return to normal activities through attentional impairment by contributing to lapses in concentration for routine and complex tasks.

Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat.

Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery. Eight days following surgery, immunohistochemistry was conducted to examine glial activation as well as evoked neuronal activation in the spinal cord. Here we document that RSD resulted in reduced weight gain and increased depressive symptoms prior to surgery. Rats exposed to RSD displayed delayed resolution of mechanical hypersensitivity in the ipsilateral paw following surgery compared to non-defeated rats. Prior exposure to RSD significantly increased microglial activation and neuronal sensitization (pERK-IR) within the ipsilateral spinal cord. In conclusion, we found that chronic social stress alters the neurobiological response to surgical injury, resulting in slowed recovery. This model maybe useful for future interventional studies examining the mechanistic interactions between depression and risk of CPSP.

Audiovisual Distraction Increases Prefrontal Cortical Neuronal Activity and Impairs Attentional Performance in the Rat.

Involvement of attentional processes is generally evidenced by disruption of behavior in the presence of distracting stimuli. The medial prefrontal cortex (mPFC) seems to play a role in fine-tuning activity during attentional tasks. A novel titration variant of the 5-choice serial reaction time task (5-choice serial reaction time titration variant [5CTV]) that adjusts task difficulty based on subject performance was used to evaluate the effects of audiovisual distraction (DSTR) on performance and mPFC single spike activity and local field potential (LFP). Attention was impaired in the 5CTV from DSTR, and mPFC spike activity was increased, whereas LFP was reduced. The increased spike activity in the mPFC in conjunction with DSTR suggests that conflicting attentional demands may contribute to the reduced task performance. As both hypo- and hyperactivation of the mPFC may contribute to attentional disruption, further studies using the 5CTV are needed to understand mPFC activity changes in real time during disruption of performance by other types of behavioral or neurobiological manipulations.

Assessment of Behavioral Disruption in Rats with Abdominal Inflammation Using Visual Cue Titration and the Five-choice Serial-reaction Time Task.

BACKGROUND: Both acute and chronic pain result in a number of behavioral symptoms in patients, including cognitive effects such as decreased attention and working memory. Intraperitoneal administration of dilute lactic acid in rodents has been used to induce abdominal inflammation and produce effects in behavioral assays of both sensory-discriminative and affective pain modalities. METHODS: Intraperitoneal injection of dilute lactic acid was used to study the impact of abdominal inflammation on an operant task requiring sustained visual attention in rats (N = 7 to 15/group) that adapts dynamically to performance ability. The effects of ketoprofen and morphine on lactic acid-induced impairment were compared with those on the disruptive effects of scopolamine. RESULTS: Lactic acid impaired performance in a concentration-dependent manner, increasing the duration of cue presentation required to maintain optimal performance from 0.5 ± 0.2 s (mean ± SD) to 17.2 ± 11.4 s after the administration of 1.8% (v/v) (N = 13). The latency to emit correct responses and to retrieve the food reward were both increased by lactic acid. All effects of lactic acid injection were reversed by both ketoprofen and morphine in a dose-dependent manner. Scopolamine, however, produced dose-dependent, nonpain-related disruption in sustained attention that was not altered by either ketoprofen or morphine. CONCLUSIONS: These data demonstrate that abdominal inflammation induced by lactic acid produces robust disruption in a visual attention-based operant task and that this disruption is reversed by analgesics. Future studies will focus on pain-related circuitry and its impact on both limbic forebrain and frontal cortical mechanisms.

Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria.

Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as ßarrestin2. We evaluated a newly developed G protein signaling-biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it produce dysphoria as determined by intracranial self-stimulation in rats. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. Moreover, the findings suggest that biased KOR agonists may present a means to treat pain and intractable itch without the side effects of dysphoria and sedation and with reduced abuse potential.

Assessment of attention threshold in rats by titration of visual cue duration during the five choice serial reaction time task.

BACKGROUND: The 5 choice serial reaction time task (5CSRTT) is commonly used to assess attention in rodents. We sought to develop a variant of the 5CSRTT that would speed training to objective success criteria, and to test whether this variant could determine attention capability in each subject. NEW METHOD: Fisher 344 rats were trained to perform a variant of the 5CSRTT in which the duration of visual cue presentation (cue duration) was titrated between trials based upon performance. The cue duration was decreased when the subject made a correct response, or increased with incorrect responses or omissions. Additionally, test day challenges were provided consisting of lengthening the intertrial interval and inclusion of a visual distracting stimulus. RESULTS: Rats readily titrated the cue duration to less than 1s in 25 training sessions or less (mean±SEM, 22.9±0.7), and the median cue duration (MCD) was calculated as a measure of attention threshold. Increasing the intertrial interval increased premature responses, decreased the number of trials completed, and increased the MCD. Decreasing the intertrial interval and time allotted for consuming the food reward demonstrated that a minimum of 3.5s is required for rats to consume two food pellets and successfully attend to the next trial. Visual distraction in the form of a 3Hz flashing light increased the MCD and both premature and time out responses. COMPARISON WITH EXISTING METHOD: The titration variant of the 5CSRTT is a useful method that dynamically measures attention threshold across a wide range of subject performance, and significantly decreases the time required for training. Task challenges produce similar effects in the titration method as reported for the classical procedure. CONCLUSIONS: The titration 5CSRTT method is an efficient training procedure for assessing attention and can be utilized to assess the limit in performance ability across subjects and various schedule manipulations.

Involvement of the lateral amygdala in the antiallodynic and reinforcing effects of heroin in rats after peripheral nerve injury.

BACKGROUND: Neuropathic pain alters opioid self-administration in rats. The brain regions altered in the presence of neuropathic pain mediating these differences have not been identified, but likely involve ascending pain pathways interacting with the limbic system. The amygdala is a brain region that integrates noxious stimulation with limbic activity. METHODS: µ-Opioid receptors were blocked in the amygdala using the irreversible antagonist, ß-funaltrexamine, and the antiallodynic and reinforcing effects of heroin were determined in spinal nerve-ligated rats. In addition, the effect of ß-funaltrexamine was determined on heroin self-administration in sham-operated rats. RESULTS: ß-Funaltrexamine decreased functional activity of µ-opioid receptors by 60 ± 5% (mean ± SD). Irreversible inhibition of µ-opioid receptors in the amygdala significantly attenuated the ability of doses of heroin up to 100 µg/kg to reverse hypersensitivity after spinal nerve ligation. Heroin intake by self-administration in spinal nerve-ligated rats was increased from 5.0 ± 0.3 to 9.9 ± 2.1 infusions/h after administration of 2.5 nmol of ß-funaltrexamine in the lateral amygdala, while having no effect in sham-operated animals (5.8 ± 1.6 before, 6.7 ± 0.9 after). The antiallodynic effects of 60 µg/kg heroin were decreased up to 4 days, but self-administration was affected for up to 14 days. CONCLUSIONS: µ-Opioid receptors in the lateral amygdala partially meditate heroin's antiallodynic effects and self-administration after peripheral nerve injury. The lack of effect of ß-funaltrexamine on heroin self-administration in sham-operated subjects suggests that opioids maintain self-administration through a distinct mechanism in the presence of pain.

Opioid self-administration in the nerve-injured rat: relevance of antiallodynic effects to drug consumption and effects of intrathecal analgesics.

BACKGROUND: Neuropathic pain is associated with several sensory abnormalities, including allodynia as well as spontaneous pain. Opioid intake in neuropathic pain patients is motivated by alleviation of both pain and allodynia. However, laboratory animal studies rely almost exclusively on reflexive withdrawal measures of allodynia. The authors examined the pharmacology of self-regulated intake of opioids in rats with or without nerve injury and compared the rate of drug intake to reversal of allodynia. METHODS: Rats were implanted with intravenous catheters, and the L5 and L6 spinal nerves were ligated in half of these animals. Rats were then trained to self-administer a commonly abused opioid (heroin) and commonly prescribed opioids (morphine, fentanyl, hydromorphone, and methadone). In addition, rats trained to self-administer heroin were given either clonidine or adenosine spinally before self-administration sessions to assess opioid-sparing effects. RESULTS: Nerve injury significantly decreased the reinforcing effects of low doses of opioids, and only doses of each opioid that reduced mechanical hypersensitivity maintained self-administration after spinal nerve ligation. The rate of drug consumption was correlated with the duration of the antiallodynic effect for each dose of opioid. Intrathecal administration of clonidine or adenosine reversed mechanical hypersensitivity, but only clonidine reduced heroin self-administration in rats with spinal nerve ligation. CONCLUSION: Opioid self-administration is significantly altered by nerve injury, with rate of drug intake being correlated with reversal of allodynia. Intrathecal clonidine, but not adenosine, produces opioid-sparing effects in self-administering rats. The neurobiologic mechanisms that regulate opioid consumption in rats therefore seem to be altered after nerve injury.

Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation.

Clonidine is approved for spinal administration against neuropathic pain, and reverses both spontaneous and elicited pain in humans following spinal administration. Rodent studies that seek to model pharmacology in pain states have historically relied on reflexive withdrawal from noxious stimuli as the primary endpoint. Drug self-administration studies have face validity in the drug abuse field for modeling drug abuse in humans, however, this methodology has not been applied to address issues related to drug seeking behaviors that may be relevant for other human populations, such as patients with neuropathic pain. Rats without spinal nerve ligation (SNL) failed to acquire intrathecal clonidine self-administration over 10 days of access. Rats were found to self-administer intrathecal infusions of clonidine following SNL in a stable and dose-responsive manner, however, and clonidine was self-administered throughout the day with 66% of total drug intake occurring during the dark cycle. Substitution of clonidine with saline or with clonidine and the alpha2-adrenoceptor antagonist idazoxan resulted in extinction of responding in SNL animals. Food reinforcement was initially decreased in SNL rats self-administering clonidine compared to normal animals, however, tolerance developed to this effect of clonidine in SNL rats after 5 days. These data demonstrate that drug self-administration can be applied to questions other than drug abuse, and provides an additional measure for development of novel therapeutic strategies for chronic pain treatment.

Differential involvement of mu-opioid receptors in the rostral versus caudal nucleus accumbens in the reinforcing effects of heroin in rats: evidence from focal injections of beta-funaltrexamine.

RATIONALE: The nucleus accumbens is a diverse and heterogeneous structure along its rostrocaudal axis. The influence of specific subpopulations of mu-opioid receptors within the NAcc in heroin self-administration has not been documented. OBJECTIVES: This study was undertaken to investigate the involvement of subregions of the NAcc in heroin self-administration in rats. METHODS: Male rats were trained to self-administer heroin and then given beta-FNA, an irreversible mu-opioid receptor antagonist, into either the rostral or caudal portion of the NAcc. RESULTS: beta-FNA (0.25-2.5 nmol) attenuated heroin self-administration in a dose-responsive manner when given into the caudal but not rostral NAcc. The number of infusions of 18 microg of heroin self-administered was increased by 50-100%. This effect persisted for up to 17 days following administration of the highest dose. These doses of beta-FNA were found to decrease [(3)H]DAMGO binding in a dose-responsive manner and the effect was confined to the NAcc, as nearby structures such as the caudate putamen and olfactory tubercles were unaffected. The effect of beta-FNA (2.5 nmol) administration into the caudal NAcc was also assessed on the dose-effect curve for heroin. This dose apparently shifted the dose-effect curve to the right initially, followed by an apparent upward shift for up to 17 days after beta-FNA administration. CONCLUSIONS: The caudal portion of the NAcc and its output sites merit further investigation regarding the reinforcing effects of heroin.