Accepted

Low back pain (LBP) is a physiologically complex and highly disabling condition with poorly understood pathophysiology. Glial reactivity has been reported in patients with chronic LBP and astrocyte reactivity has been suggested as a potential contributor to LBP chronicity. Spinal mobilization (SM) is a non-pharmacological approach with mild to moderate efficacy in treating LBP but physiological mechanisms responsible are unknown.

Chronic visceral pain (CVP) is a prevalent and debilitating syndrome with limited treatments. Guanylyl cyclase C (GUCY2C) is the receptor for uroguanylin (GUCA2B) in small intestine and guanylin (GUCA2A) in colorectum. This hormone-receptor axis produces cyclic (c)GMP accumulation, inducing intestinal fluid secretion. This forms the basis for use of GUCY2C agonists linaclotide and plecanatide to treat constipation-type irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Unexpectedly, GUCY2C agonists relieve CVP in these patients, and in mouse models of visceral pain. Interestingly, these patients are deficient in uroguanylin, suggesting that constipation and CVP may reflect hormone insufficiency silencing GUCY2C. Indeed, eliminating GUCY2C in mice (GUCY2C ) produced CVP, evoked by cyclic rectal distension, quantified by the abdominal withdrawal reflex and by phospho-ERK signaling in the spinal cord dorsal horn. CVP severity in GUCY2C mice recapitulated TNBS-induced inflammatory bowel disease in wild type (GUCY2 ) mice. Oral linaclotide relieved TNBS-induced CVP in wild type mice, but was without effect on CVP in GUCY2C mice. The mechanistic basis of GUCY2C-dependent visceral analgesia remains obscure. While GUCY2C is expressed by all epithelial cells in intestine, a GUCY2C promoter-driven GFP reporter revealed a novel rare population of cells enriched in GUCY2C mRNA, protein, and activity. GUCY2C cells, concentrated in duodenum but rare in rectum, morphologically resemble enteroendocrine cells with a basal neuropod potentially synapsing on visceral afferents in the lamina propria, offering a cellular substrate for GUCY2C visceral nociceptive signaling. RNAseq analysis revealed that GUCY2C neuropod cells were deficient in gene products canonically associated with GUCY2C-driven secretion, including GUCA2A, GUCA2B, CFTR and NHE3. Rather, these cells were enriched in gene sets characteristic of neurons. Importantly, dorsal root ganglia (DRG) cells formed functional connections with GUCY2C neuropod cells in co-culture. Thus, DRG cells with GUCY2C neuropod cells alone (GUCA2B-deficient, GUCY2C silenced) were hyperexcitable following current injection, with a reduced rheobase and repetitive action potentials (APs). In contrast, adding linaclotide (hormone replete, GUCY2C activated) silenced DRG neuron excitability, raising the rheobase and eliminating repetitive APs. DRG neuron excitability was not affected by linaclotide in co-cultures with neuropod cells from GUCY2C mice. Moreover, the effects of linaclotide on DRG neuron excitability was not recapitulated by extracellular cGMP. These observations suggest that GUCY2C neuropod cells synapse with DRG visceral afferents and modulate their excitability. They support a model in which GUCA2B sufficiency activates GUCY2C to suppress DRG neuron excitability, while GUCA2B insufficiency silences GUCY2C to produce DRG hyperexcitability and CVP. Finally, they suggest that linaclotide relieves CVP by stimulating GUCY2C neuropod cells to inhibit DRG excitability and nociceptive signaling.

Chronic pain is a debilitating condition leading to impaired quality of life but has few efficacious therapeutic options. The use of opioids to treat chronic pain is associated with well-known drawbacks including drug dependence and addiction. The development of opioid alternatives to treat chronic pain is an urgent, yet unmet, need. Here we show the therapeutic potential of GPR171, a G-Protein Coupled Receptor that was recently identified to regulate morphine antinociception. Previously shown that systemic administration of the GPR171 agonist, MS15203, enhances morphine antinociception in acute pain tests in mice. Here, we show that once-daily systemic administration of MS15203 (10 mg/kg, i.p.) over the course of 1 week improved chronic pain outcomes in two different mouse pain models. Chemotherapy-induced peripheral neuropathy (CIPN) was induced by injecting Paclitaxel (16 mg/kg cumulative) and inflammatory pain was induced by injecting Complete Freund's Adjuvant (CFA) under the epidermis into the plantar surface of both hind paws (20 µl/paw). MS15203 improved mechanical allodynia caused by CIPN and reduced thermal hypersensitivity caused by CFA-induced inflammatory pain. The reduction of chronic pain duration was observed only in male mice, but not in female mice, indicating a sex-dependent effect at this particular dose of GPR171 agonist. Analysis of GPR171 protein levels in the midbrain Periaqueductal Gray showed that neuropathic pain decreased GPR171 receptor levels in males, but treatment by MS15203 rescued this decrease. Taken together, our findings show that GPR171 activity exhibits sexual dimorphism and can regulate multiple modalities of chronic pain.

Myofascial pain and myofascial pain syndromes are among some of the most common acute and chronic pain conditions. Many interventional procedures can be performed in both an acute and chronic pain setting to address myofascial pain syndromes. Trigger point injections can be performed with or without imaging guidance such as fluoroscopy and ultrasound; however, the use of imaging in years past has been recommended to improve patient outcome and safety. Injections can be performed using no injectate (dry needling), or can involve the administration of local anesthetics, botulinum toxin, or corticosteroids.

Despite the widespread clinical use of acupuncture in painful situations, the use of this treatment should be further clarified. Nociception is mediated by the activation of nociceptors, such as transient receptor potentials (TRPs). The family of TRPs includes TRPV1, TRPM8, and TRPA1, which can be stimulated by substances such as capsaicin, menthol, and methyl salicylate, respectively.

The strong need for a new foundational molecular framework for human nervous system research at the nociceptive level is now matched by comprehensive and quantitative capabilities for analyzing nociceptive tissues such as pathological peripheral tissue, damaged peripheral nerve, dorsal root ganglia, spinal cord, and brain, where possible. However, this idea must be matched by equally strong organization and infrastructures for multisite tissue recovery, molecular analyses, data sharing, and long-term archiving. Experience from other human tissue analysis projects shows that a decades long activity may be expected, hence "Be in it for the long haul." While certain milestones can be met fairly quickly, others aimed at molecular and neuroanatomical characterization of chronic pain disorders will require the sustained attention of the groups involved. This can yield a valuable addition to basic and translational pain research and the development of new treatments whose targets are validated directly in humans. Perspective: A concerted effort is needed to build human nociceptive tissue banks for multi-omic research. In addition to collecting tissue, a careful characterization of pain problems from donors is essential, as is a parallel effort to assess their concurrent medical problems, medications, and the many variables of general human activity and lifestyle that can impact the results. Given the projected long time frame, in addition to maintaining funding, sustaining motivation and momentum are critical factors for success.

The major therapeutic challenge in inflammatory rheumatic diseases is the persistence of pain despite good responses to specific therapies. Central sensitization, which can be assessed clinically by psychophysical measurements, including quantitative sensory testing (QST), is a widely proposed mechanism for chronic pain. In this systematic review, we explored the scientific literature addressing quantitative sensory testing in inflammatory rheumatic diseases. We searched Pubmed and Embase for publications up to December 2021 concerning studies on quantitative sensory testing focusing on pain thresholds, temporal summation (TS) and conditioned pain modulation (CPM), in adult patients with chronic inflammatory rheumatism (e.g. rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis). The exclusion criteria were reviews, inclusion of children and no reported pain threshold. Data quality was assessed with the National Institutes of Health (NIH) Quality Assessment tools. We identified 27 studies (18 controlled, 9 uncontrolled) including 1875 patients with inflammatory rheumatic diseases and 795 controls. A decrease in pressure pain threshold, in favor of allodynia, was found in 12 of 14 controlled studies on patients with rheumatoid arthritis and spondyloarthritis. The results of other psychophysical tests, including TS and CPM, were inconsistent due to population heterogeneity and a lack of standardization of the patients' disease duration, activity and treatment. Our review shows that pain in chronic inflammatory rheumatism is associated with pressure allodynia. However, given the heterogeneous quality and discrepant results of studies of other QST outcome measures, the hypothesis of central sensitization involvement in pain processing in these patients cannot be confirmed.

Itch is an unpleasant sensation that induces the desire to scratch. Except for a sketchy map focusing on neural mechanisms underlying itch processing being drawn at the peripheral and spinal level over the past decade, the brain mechanisms remain poorly understood. Several previous studies indicated that anterior cingulate cortex (ACC) and prelimbic cortex (PrL), two subregions of the medial prefrontal cortex (mPFC) play an important role in regulating itch processing. However, the knowledge about whether infralimbic cortex (IL), another subregion of mPFC, is involved in modulating itch processing remains unclear. Here, we showed that the activity of IL excitatory pyramidal neurons was significantly elevated during itch-related scratching, and pharmacogenetic inhibition of IL pyramidal neurons significantly impaired itch-related scratching. Moreover, IL-medial striatum (MS) projections were verified as a critical neural pathway for modulating itch processing. Therefore, the present study firstly presents the regulatory function of IL pyramidal neurons during itch processing and also reveals that IL-MS projections are involved in modulating the itch processing.