Accepted

The aim of this review is to draw attention to neurosurgical approaches for treating chronic and opioid-resistant pain. In a first chapter, an up-to-date overview of the main pathophysiological mechanisms of pain has been carried out, with special emphasis on the details in which the surgical treatment is based. In a second part, the principal indications and results of different surgical approaches are reviewed. Cordotomy, Myelotomy, DREZ lesions, Trigeminal Nucleotomy, Mesencephalotomy, and Cingulotomy are revisited. Ablative procedures have a limited role in the management of chronic non-cancer pain, but they continues to help patients with refractory cancer-related pain. Another ablation lesion has been named and excluded, due to lack of current relevance. Peripheral Nerve, Spine Cord, and the principal possibilities of Deep Brain and Motor Cortex Stimulation are also revisited. Regarding electrical neuromodulation, patient selection remains a challenge.

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 – ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2'-3'-dideoxycitidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance. AM1710 and LY2828360 alleviated ddC-induced neuropathic nociception in mice of both sexes. These benefits were absent in global CB2 knockout mice, which exhibited robust morphine antinociception. Like morphine, AM1710 blunted ddC-induced increases in proinflammatory cytokine (IL-1β, TNF-α) and chemokine (CCL2) mRNA expression levels. We generated advillin;CB2 conditional knockout mice to ascertain the role of CB2 localized to primary sensory neurons in CB2-mediated therapeutic effects. Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillin;CB2 mice, which exhibited robust ddC-induced neuropathy. In ddC-treated CB2 mice, LY2828360 suppressed development of morphine tolerance and reversed established morphine tolerance, albeit with greater efficacy in male compared to female mice. LY2828360 failed to block or reverse morphine tolerance in advillin;CB2 mice. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

The aim of this study was to explore differential psychological profiles among patients with chronic pain with and without fibromyalgia, and to determine the results of the cognitive behavioral therapy (CBT) for pain. Thirty patients with chronic pain and 60 patients with fibromyalgia were referred to 10 weekly sessions of CBT in a general hospital and were evaluated in pain-related variables, psychopathological symptoms, coping strategies, resilience, and quality of life. The program was implemented in specific groups for patients with fibromyalgia and nonfibromyalgia chronic pain. After the intervention, patients with fibromyalgia showed higher levels of psychopathology, rated their health status as poorer, and presented larger amplification of symptoms, higher levels of somatization, a more ruminating style of thinking and greater distress. Patients without fibromyalgia achieved better therapeutic results in both pain intensity (d = 0.39 vs. d = 0.12) and psychopathological distress (d = 0.77 vs. d = 0.11) compared to patients with fibromyalgia. Therefore, differential profiles and limited therapeutic results in fibromyalgia patients suggest the need to outline differentiated treatments and include other therapeutic strategies.

Cancer pain is the most prevalent symptom experienced by cancer patients. It substantially impacts a patient's long-term physical and emotional health, making it a pressing issue that must be addressed. Purinergic receptor P2X7 (P2X7R) is a widely distributed and potent non-selective ATP-gated ion channel that regulates tumor proliferation, chronic pain, and the formation of inflammatory lesions in the central nervous system. P2X7R plays an essential role in cancer pain and complications related to cancer pain including depression and opioid tolerance. This review focuses on the structure and distribution of P2X7R, its role in diverse tissues in cancer pain, and the application of P2X7R antagonists in the treatment of cancer pain to propose new ideas for cancer pain management.

Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity.

Our previous study has illuminated that PGC-1α downregulation promoted chronification of pain after burn injury. RNA-seq analysis predicted association between Sp1 and chronic constriction injury (CCI)-provoked neuropathic pain. Further ChIP-Atlas data investigation suggested the binding to Sp1 to PGC-1α. Thereby, we performed this study to illustrate the functional relevance of the Sp1/PGC-1α axis in neuropathic pain.

Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care.

To review the current state of pharmaceutical treatment recommendations for the management of osteoarthritis.

The current study explored the antinociceptive activity of magnolol in post-incisional inflammatory nociceptive pain.

The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. We hypothesize, that performing multi-omic analyses during CPT gives the opportunity to home in on molecular mechanisms involved. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken. RNA-Sequencing, steroid profiling and untargeted metabolomics were performed. Each 'omic level was analyzed separately at both single-feature and systems-level (principal component [PCA] and partial least squares [PLS] regression analysis) and all 'omic levels were combined using an integrative multi-omics approach, all using the paired-sample design.