Chaoling Qu

Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry

Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward–valuation circuitry.

Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy

&NA; Neuropathic pain is often “spontaneous” or “stimulus‐independent.” Such pain may result from spontaneous discharge in primary afferent nociceptors in injured peripheral nerves. However, whether axotomized primary afferent nociceptors give rise to pain is unclear. The rostral anterior cingulate cortex (rACC) mediates the negative affective component of inflammatory pain. Whether the rACC integrates the aversive component of chronic spontaneous pain arising from nerve injury is not known. Here, we used the principle of negative reinforcement to show that axotomy produces an aversive state reflecting spontaneous pain driven from injured nerves. Additionally, we investigated whether the rACC contributes to the aversiveness of nerve injury‐induced spontaneous pain. Partial or complete hind paw denervation was produced by sciatic or sciatic/saphenous axotomy, respectively. Conditioned place preference resulting from presumed pain relief was observed following spinal clonidine in animals with sciatic axotomy but not in sham‐operated controls. Similarly, lidocaine administration into the rostral ventromedial medulla (RVM) produced place preference selectively in animals with sciatic/saphenous axotomy. In rats with spinal nerve ligation (SNL) injury, lesion of the rACC blocked the reward elicited by RVM lidocaine but did not alter acute stimulus‐evoked hypersensitivity. Lesion of the rACC did not block cocaine‐induced reward, indicating that rACC blockade did not impair memory encoding or retrieval but did impair spontaneous aversiveness. These data indicate that spontaneous pain arising from injured nerve fibers produces a tonic aversive state that is mediated by the rACC. Identification of the circuits mediating aversiveness of chronic pain should facilitate the development of improved therapies. Spontaneous pain arising from injured nerve fibers produces a tonic aversive state that is mediated by the rostral anterior cingulate cortex.

Contribution of Afferent Pathways to Nerve-injury Induced Spontaneous Pain and Evoked Hypersensitivity

Summary TRPV1 fibers and spinal NK‐1 expressing ascending projections mediate spontaneous pain and evoked hypersensitivity. Large‐diameter ascending projections mediate tactile hypersensitivity. ABSTRACT A predominant complaint in patients with neuropathic pain is spontaneous pain, often described as burning. Recent studies have demonstrated that negative reinforcement can be used to unmask spontaneous neuropathic pain, allowing for mechanistic investigations. Here, ascending pathways that might contribute to evoked and spontaneous components of an experimental neuropathic pain model were explored. Desensitization of TRPV1‐positive fibers with systemic resiniferatoxin (RTX) abolished spinal nerve ligation (SNL) injury‐induced thermal hypersensitivity and spontaneous pain, but had no effect on tactile hypersensitivity. Ablation of spinal NK‐1 receptor‐expressing neurons blocked SNL‐induced thermal and tactile hypersensitivity as well as spontaneous pain. After nerve injury, upregulation of neuropeptide Y (NPY) is observed almost exclusively in large‐diameter fibers, and inactivation of the brainstem target of these fibers in the nucleus gracilis prevents tactile but not thermal hypersensitivity. Blockade of NPY signaling within the nucleus gracilis failed to block SNL‐induced spontaneous pain or thermal hyperalgesia while fully reversing tactile hypersensitivity. Moreover, microinjection of NPY into nucleus gracilis produced robust tactile hypersensitivity, but failed to induce conditioned place aversion. These data suggest that spontaneous neuropathic pain and thermal hyperalgesia are mediated by TRPV1‐positive fibers and spinal NK‐1‐positive ascending projections. In contrast, the large‐diameter dorsal column projection can mediate nerve injury‐induced tactile hypersensitivity, but does not contribute to spontaneous pain. Because inhibition of tactile hypersensitivity can be achieved either by spinal manipulations or by inactivation of signaling within the nucleus gracilis, the enhanced paw withdrawal response evoked by tactile stimulation does not necessarily reflect allodynia.

The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: A novel pain modulation pathway

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG-brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm-VLO-PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-delta and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of mu-opioid receptors, serotonin 1(A) receptors, and dopamine D(2)-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.

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. 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.

Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain

TOC summary PKMζ‐dependent amplification contributes to nerve injury‐induced aversiveness within the rostral anterior cingulate cortex and to evoked, but not spontaneous, pain in the spinal cord. ABSTRACT Injuries can induce adaptations in pain processing that result in amplification of signaling. One mechanism may be analogous to long‐term potentiation and involve the atypical protein kinase C, PKMζ. The possible contribution of PKMζ‐dependent and independent amplification mechanisms to experimental neuropathic pain was explored in rats with spinal nerve ligation (SNL) injury. SNL increased p‐PKMζ in the rostral anterior cingulate cortex (rACC), a site that mediates, in part, the unpleasant aspects of pain. Inhibition of PKMζ within the rACC by a single administration of ζ‐pseudosubstrate inhibitory peptide (ZIP) reversed SNL‐induced aversiveness within 24 hours, whereas N‐methyl‐D‐aspartate receptor blockade with MK‐801 had no effects. The SNL‐induced aversive state (reflecting “spontaneous” pain), was re‐established in a time‐dependent manner, with full recovery observed 7 days post‐ZIP administration. Neither rACC ZIP nor MK‐801 altered evoked responses. In contrast, spinal ZIP or MK‐801, but not scrambled peptide, transiently reversed evoked hypersensitivity, but had no effect on nerve injury‐induced spontaneous pain. PKMζ phosphorylation was not altered by SNL in the spinal dorsal horn. These data suggest that amplification mechanisms contribute to different aspects of neuropathic pain at different levels of the neuraxis. Thus, PKMζ‐dependent amplification contributes to nerve injury‐induced aversiveness within the rACC. Moreover, unlike mechanisms maintaining memory, the consequences of PKMζ inhibition within the rACC are not permanent in neuropathic pain, possibly reflecting the re‐establishment of amplification mechanisms by ongoing activity of injured nerves. In the spinal cord, however, both PKMζ‐dependent and independent mechanisms contribute to amplification of evoked responses, but apparently not spontaneous pain.

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: A potential biomarker of efficacy

Summary Relief of ongoing pain may be reflected by increased dopamine efflux in the nucleus accumbens, providing a neurochemical efficacy measure for evaluation of novel analgesics. ABSTRACT Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti‐inflammatory drugs (NSAIDs), were evaluated in models of post‐surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham‐operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose‐related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post‐surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain‐relieving mechanisms.

D2-like but not D1-like dopamine receptors are involved in the ventrolateral orbital cortex-induced antinociception: A GABAergic modulation mechanism

The ventrolateral orbital cortex (VLO) is part of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius (Sm) and a descending pathway to the spinal cord relaying in the periaqueductal gray (PAG). This study examines whether activation of D(1)-like and D(2)-like dopamine receptors in VLO produces antinociception and whether GABAergic modulation is involved in the VLO, D(2)-like dopamine receptor activation-evoked antinociception. The radiant heat-evoked tail flick (TF) reflex was used as an index of nociceptive response in lightly anesthetized rats. Microinjection of the D(2)-like (D(2)/D(3)) dopamine receptor agonist quinpirole (0.1-2.0 microg), but not D(1)-like (D(1)/D(5)) receptor agonist SKF-38393 (1.0, 5.0 microg), into VLO produced dose-dependent antinociception which was antagonized by the D(2)-like (D(2)/D(3)) receptor antagonist raclopride (1.5 microg). We also found that VLO application of the GABA(A) receptor antagonist bicuculline or picrotoxin (100 ng) enhanced the quinpirole-induced inhibition of the TF reflex, whereas the GABA(A) receptor agonist muscimol (250 ng) or THIP (1.0 microg) significantly attenuated the quinpirole-induced inhibition. These results suggest that D(2)-like, but not D(1)-like, dopamine receptors are involved in VLO-induced antinociception and that GABAergic disinhibitory mechanisms participate in the D(2)-like receptor mediated effect. These findings provide support for the hypothesis that D(2)-like receptor activation may inhibit the inhibitory action of the GABAergic interneurons on the output neurons projecting to PAG leading to activation of the brainstem descending inhibitory system and depression of nociceptive inputs at the spinal dorsal horn.

GABAergic modulation is involved in the ventrolateral orbital cortex 5-HT1A receptor activation-induced antinociception in the rat

Abstract The ventrolateral orbital cortex (VLO) is a component of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius (Sm) and a descending pathway relaying in the periaqueductal gray matter (PAG). This study examines whether the activation of 5‐HT1A receptors in VLO produces antinociception and whether GABAergic modulation is involved in the VLO 5‐HT1A receptor activation‐evoked antinociception. The radiant heat‐evoked tail flick (TF) reflex was used as an index of nociceptive response in lightly anesthetized rats. Microinjection of the 5‐HT1A receptor agonist 8‐OH‐DPAT (1.0, 2.0, 5.0 μg) into VLO produced dose‐dependent antinociception, which was reversed by the 5‐HT1A receptor antagonist (NAN‐190, 20 μg). We also found that VLO application of the GABAA receptor antagonist bicuculline or picrotoxin (100 ng) enhanced the 8‐OH‐DPAT‐induced inhibition of the TF reflex, whereas the GABAA receptor agonist muscimol (250 ng) or THIP (1.0 μg) significantly attenuated the 8‐OH‐DPAT‐induced inhibition. These results suggest that 5‐HT1A receptors are involved in VLO‐induced antinociception and that GABAergic disinhibitory mechanisms participate in the 5‐HT1A receptor‐mediated effect. These findings provide support for the hypothesis that 5‐HT1A receptor activation may inhibit the inhibitory action of the GABAergic interneurons on the output neurons projecting to PAG leading to activation of the brainstem descending inhibitory system and depression of nociceptive inputs at the spinal cord level.

The role of dopamine receptors in ventrolateral orbital cortex-evoked anti-nociception in a rat model of neuropathic pain.

The present study examined the role of dopamine and D(1)-and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked anti-hypersensitivity in a rat model of neuropathic pain, as well as the possible underlying mechanisms. Results showed that microinjection of apomorphine [(R(-)-apomorphine hydrochloride)], a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (1.5 microg), but was enhanced by the D(1)-like dopamine receptor antagonist SCH23390 (R(+)-SCH-23390 hydrochloride, 5.0 microg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D(2)-like dopamine receptor agonist quinpirole [((-)-quinpirole hydrochloride, 0.5, 1.0, and 2.0 microg)]. In addition, microinjection of larger doses (10 and 20 microg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABA(A) receptor antagonists, bicuculline [(+)-bicuculline,(S), 9(R)] and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5 microg)-induced anti-allodynia. In contrast, GABA(A) receptor agonists, muscimol hydrochloride (250 ng) or THIP [(2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride, 1.0 microg)], blocked quinpirole (2.0 microg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D(2)-like dopamine receptors, and inhibition of D(1)-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D(2)-like receptor mediating effects in neuropathic pain.