Third Special Issue on Mechanisms of Pain and Itch

We have published two special issues on pain and itch in Neuroscience Bulletin that cover their peripheral, central, and glial mechanisms [1, 2]. The first special was published in 2012 [1], highlighting several topics such as Toll-like receptors, capsaicin receptor TRPV1, interaction of μ- and δ-opioid receptors, and population coding of somatic sensations. In 2018, we published the second special issue [2], which covered a wide breath of research, including molecular and functional characterization of primary sensory neurons, neurocircuits of pain and itch, Na⁺ channel expression in human sensory neurons, modulation of pain and itch by spinal glia, infection, sex dimorphisms in pain, TRP channels in pain and itch, in vivo Ca²⁺ imaging in the investigation of pain mechanisms, spinal cord mechanisms of itch transmission, modeling pain using fMRI, and empathy in pain. In parallel with many breakthroughs in neuroscience research, we have seen further progress in several frontiers in pain and itch since 2018. It is timely to highlight the new advances in this third special issue.

Accumulating evidence supports a critical role of spinal cord astrocytes in the pathogenesis of pain and itch [3]. The ATP receptor P2X7 is induced in microglial cells in multiple brain regions after epilepsy [4]. However, the epigenetic modulation of P2X7 in astrocytes is not well known. Using an animal model of visceral pain in adult rats with neonatal colonic inflammation, Xu’s group demonstrated an epigenetic modulation of P2X7 by which DNA demethylation of the P2x7r locus guided by the transcription factor GATA binding protein 1 in spinal astrocytes contributes to chronic visceral pain [5]. This study has clinical relevance by revealing a central mechanism of irritable bowel syndrome and novel therapeutic targets for this disease.

The anterior cingulate cortex (ACC) plays a critical role in regulating the emotional and sensory aspects of pain, but it remains unclear how the ACC regulates hyperalgesia and anxiety. Chronic pancreatitis (CP) is a severe pain condition and previous studies have focused on primary sensory neurons and the spinal cord. Li’s research team investigated the glutamate receptor mechanisms of CP by microinjection of NMDA and AMPA receptor antagonists into the ACC. In this study, CP was induced by intraductal administration of trinitrobenzene sulfonic acid, and this model resulted in long-term abdominal hyperalgesia and anxiety in rats. Using chemogenetics, the authors found that specific inhibition of ACC pyramidal cells not only reduced the hyperalgesia but also alleviated anxiety, a major comorbidity of chronic pain in male Sprague-Dawley rats [6]. This study further supported an important role of the ACC in the regulation of pain and anxiety. It will be of great interest to test female animals in the same model since females suffer more chronic pain and emotional distress.

Optogenetic approaches have greatly expanded our knowledge of the central and peripheral nervous systems. In a review article, Chen, Zhang, and colleagues highlight the importance of optogenetic approaches in studying the neurocircuits of pain [7]. The authors review commonly-used excitatory and inhibitory opsins and discuss the contributions of different brain regions to different aspects of pain. Notably, optogenetic approaches have also been extensively used to study the neurocircuits of itch. It is important to discuss the limitations of current optogenetic approaches.

TRP channels such as TRPV1 and TRPM8 are molecular sensors of temperature and pain. Their discovery led to a Nobel Prize in Physiology or Medicine in 2021 [8]. Previous studies on pain and itch have focused on TRPA1, TRPV1, TRPV4, and TRPM8 [9]. For example, TRPA1 is implicated in oxidative stress-induced itch [10]. Little is known about the contribution of TRPC channels in itch modulation. Mitochondria are the major sources of reactive oxygen species (mROS) and mitochondrial dysfunction results in sensory abnormalities such as painful diabetic neuropathy. Although mROS have been linked to TRPC3, it is unclear how TRPC3 regulates itch. Using a mouse cheek model of dry skin-induced chronic itch, Oh’s team demonstrated that TRPC3 but not TRPA1 and TRPV1 contributes to dry skin-induced itch. They also showed increased mROS levels in the dry skin [11]. Therefore, TRPC3 may serve as a new therapeutic target for itch.

Myocardial ischemia (MI) causes referred pain in somatic body regions, such as the chest, left upper arm, and upper back. It is generally believed that cardiac referred pain results from the convergence of cardiac and somatic inputs in the thoracic spinal cord. Interestingly, MI also manifests as sympathetic hyperexcitation. In this issue, Zhu, Gao, and colleagues demonstrate a novel sympathetic-sensory coupling after MI in rats [12]. They also show mechanical pain in the forelimb and upper-back following MI. Furthermore, their findings indicate that sensory inputs contribute to altered cardiac function via peripheral α₂AR-mediated sympathetic-sensory coupling. Notably, tyrosine hydroxylase is also expressed by thoracic DRG neurons in mice, highlighting possible species differences between mice and rats.

Parkin is an E3 ubiquitin ligase and has been widely implicated in neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. A previous study by a Japanese group reported down-regulation of Parkin in DRG sensory neurons under a neuropathic pain condition. However, the role of Parkin in sensory neurons remains unclear. Zhang and coworkers highlight a protective role of Parkin in sensory neurons against chronic pain. They show that Parkin mRNA is significantly decreased in DRGs after chronic inflammation [13]. Importantly, overexpression of Parkin in sensory neurons via AAV injection is sufficient to alleviate mechanical allodynia after inflammation, nerve injury, and chemotherapy. The molecular targets of Parkin remain to be verified.

Electroacupuncture (EA) has been shown to induce analgesia by releasing endogenous opioid peptides in the CNS. Previous work from Han’s group has demonstrated that opioid peptide release by EA is frequency-dependent: low frequency (2 Hz) stimulation releases encephalin that activates μ-opioid and δ-opioid receptors, whereas high frequency stimulation releases dynorphin that activates the κ-opioid receptor [14]. Spinal cord stimulation (SCS) has been used to treat chronic pain in patients for whom other treatments have failed. SCS also alleviates neuropathic pain in animals after nerve injury and spinal cord injury [15]. Since primary afferent fibers (such as large Aβ-fibers) can be activated either by EA or SCS for pain suppression, Han’s group tested the hypothesis that SCS also induces analgesia by releasing opioid peptides to activate the endogenous opioid system [16]. Strikingly, the authors found that various frequencies of SCS (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) have similar analgesic effects in reducing nerve injury-induced allodynia but μ, δ, or κ receptor antagonists have different effects on reversing the SCS-induced analgesia [16]. This study highlights the shared analgesic mechanism of different forms of neuromodulation (EA and SCS) through activation of the endogenous opioid system.

Sympathetic regulation has been well implicated in the pathogenesis of pain, but it remains unknown how the sympathetic system regulates chronic pain. Using a mouse model of chronic itch induced by cutaneous T cell lymphoma (CTCL) [17], Han and colleagues show remarkable scratching behavior and activation of microglia and astrocytes in the spinal cord in this lymphoma model. Strikingly, sympathetic blockade effectively suppresses glial activation and chronic itch [18]. Unlike previous studies showing sympathetic control in the peripheral nervous system, this study has revealed a novel mechanism by which sympathetic modulation in the CNS controls the function of glial cells.

The mechanisms of anesthetics have been a central theme of research on anesthesia and pain. A recent EEG study showed that propofol modulates cortico-cortical functional connectivity in the human brain [19]. It is well established that anesthetics affect GABAergic neurotransmission to induce anesthesia and suppress pain. Recently, programmed death protein 1 (PD-1), an immune checkpoint inhibitor, was shown to promote the emergence of anesthesia via the modulation of GABAergic neurotransmission in the brain, raising the possibility that anti-PD-1 immunotherapy may impair anesthesia [20]. General anesthetics also activate a potent central pain-suppression circuit in the amygdala [21]. In this issue, Song et al. report a new pathway to mediate anesthesia. Specifically, they demonstrate that dopaminergic neurons in the ventral tegmental–prelimbic pathway promote the emergence of sevoflurane anesthesia in rats [22].

We also include two research highlights, one by Tan et al. that highlights the macrophage IL-23/IL-17A pathway in regulating mechanical pain in females [23], and another by Yan et al. that highlights a spinal–parabrachial–mesencephalic circuit [24], offering new mechanistic insight into pain-induced emotional distress and a connection between pain and reward [25]. The majority of preclinical studies have been conducted in male animals and several male-specific cell types and signaling pathways have been revealed [26]. It is of great interest to demonstrate a female-dominant pain pathway, which is mediated by the macrophage IL-23/IL-17A pathway that activates IL-17R receptor on nociceptive neurons in females through neuro-immune interactions [27].

In summary, the third special issue presented here will further our understanding of pain and itch regulation in health and disease. These preclinical studies in clinically relevant animal models will drive translational studies to develop more efficacious and safe therapeutics for the relief of pain and itch.