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The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.
Learn More >Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone (TT) and associated symptoms. The effect of testosterone replacement therapy (TRT) on muscle function in men with chronic pain and low TT remains to be investigated.
Learn More >Occipital headache, the perception of pain in the back of the head, is commonly described by patients diagnosed with migraine, tension-type headache, and occipital neuralgia. The greater and lesser occipital nerves play central role in the pathophysiology of occipital headache. In the clinical setup, such headaches are often treated with onabotulinumtoxinA, a neurotoxin capable of disrupting ability of nociceptors to get activated and/or release proinflammatory neuropeptides. Attempting to understand better onabotulinumtoxinA mechanism of action in reducing headache frequency, we sought to determine its effects on expression of inflammatory genes in injected occipital tissues. To achieve this goal, we injected 40 units of onabotulinumtoxinA into 4 muscle groups (occipitalis, splenius capitis, semispinalis capitis, and trapezius muscles – all located on one side of the occiput) of patients with chronic bilateral occipital headache scheduled for occipital nerve decompression surgery 1-month latter. At the time of surgery, we collected discarded muscle, fascia and periosteum tissues from respective locations on both sides of the neck and occiput and performed targeted transcriptome analyses to determine expression level of inflammatory genes in onabotulinumtoxinA-injected and onabotulinumA-uninjected tissues. We found that (a) onabotulinumtoxinA alters expression of inflammatory genes largely in periosteum, minimally in muscle and not at all in fascia; (b) expression of inflammatory genes in uninjected periosteum and muscle is significantly higher in historical onabotulinumA responders than historical non-responders; (c) in historical responders' periosteum, onabotulinumA decreases expression of nearly all significantly altered genes, gene sets that define well-recognized inflammatory pathways (e.g., pathways involved in adaptive/innate immune response, lymphocyte activation, and cytokine, chemokine, NF-kB, TNF and interferon signaling), and abundance of 12 different immune cell classes (e.g., neutrophils, macrophages, cytotoxic T-, NK-, Th1-, B- and dendritic-cells), whereas in historical non-responders it increases gene expression but to a level that is nearly identical to the level observed in the uninjected periosteum and muscle of historical responders, and surprisingly, (d) that the anti-inflammatory effects of onabotulinumA are far less apparent in muscles and absent in fascia. These findings suggest that in historical responders' periosteum – but not muscle or fascia – inflammation contributes to the pathophysiology of occipital headache, and that further consideration should be given to the possibility that onabotulinumA mechanism of action in migraine prevention could also be achieved through its ability to reduce pre-existing inflammation, likely through localized interaction that lead to reduction in abundance of immune cells in the calvarial periosteum.
Learn More >While opioids produce both analgesia and side-effects by action at mu-opioid receptors (MOR), at spinal and supraspinal sites, potency of different opioids to produce these effects vary. While it has been suggested that these differences might be due to bias for signaling via β-arrestin versus G protein alpha (Gα), recent studies suggest that G protein biased MOR agonists still produce clinically important side-effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gα subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gα2, Gα3 and Gα markedly attenuated hyperalgesia induced by sub-analgesic dose (sub-AD) fentanyl, while AS-ODN for Gα1, as well as Gα2 and Gα3, but not Gα, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gα1 and Gα2 unexpectedly analgesia induced by analgesic dose (AD) fentanyl, while Gα1 AS-ODN markedly AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E (PGE)-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gα3 and Gα AS-ODN-treated rats, respectively. In contrast, none of the Gα AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gα subunits is necessary for the analgesia and side-effects of two of the most clinically used opioid analgesics. Design of opioid analgesics that demonstrate selectivity for individual Gα may produce a more limited range of side-effects and enhanced analgesia. Biased mu-opioid receptor (MOR) agonists that preferentially signal through G proteins α-subunits over β-arrestins have been developed, as an approach to mitigate opioid side-effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense (AS-ODN) to different Gα subunits play a role in hyperalgesia and analgesia induced by sub-analgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G protein α-subunits.
Learn More >The study had been initiated because of restrictions put in place to control the spread of coronavirus in Milan in March 2020 that impacted clinical activities at our tertiary headache center in Milan (Foundation IRCSS Carlo Besta Neurological Institute). Treatment efforts were modified to make use of telephonic and internet communication to maintain care of our patients.
Learn More >Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes.
Learn More >Crotalphine (CRP) is a structural analogue to a peptide that was first identified in the crude venom from the South American rattlesnake . This peptide induces a potent and long-lasting antinociceptive effect that is mediated by the activation of peripheral opioid receptors. The opioid receptor activation regulates a variety of intracellular signaling, including the mitogen-activated protein kinase (MAPK) pathway. Using primary cultures of sensory neurons, it was demonstrated that crotalphine increases the level of activated ERK1/2 and JNK-MAPKs and this increase is dependent on the activation of protein kinase Cζ (PKCζ). However, whether PKCζ-MAPK signaling is critical for crotalphine-induced antinociception is unknown. Here, we biochemically demonstrated that the systemic crotalphine activates ERK1/2 and JNK and decreases the phosphorylation of p38 in the lumbar spinal cord. The in vivo pharmacological inhibition of spinal ERK1/2 and JNK, but not of p38, blocks the antinociceptive effect of crotalphine. Of interest, the administration of a PKCζ pseudosubstrate (PKCζ inhibitor) prevents crotalphine-induced ERK activation in the spinal cord, followed by the abolishment of crotalphine-induced analgesia. Together, our results demonstrate that the PKCζ-ERK signaling pathway is involved in crotalphine-induced analgesia. Our study opens a perspective for the PKCζ-MAPK axis as a target for pain control.
Learn More >Aquaporins (AQPs) play critical physiological roles in water balance in the central nervous system (CNS). Aquaporin-4 (AQP4), the principal aquaporin expressed in the CNS, has been implicated in the processing of sensory and pain transmission. Akt signaling is also involved in pain mediation, such as neuroinflammatory pain and bone cancer pain. Previously, we found that expression of AQP4 and p-Akt was altered in the rat spinal cord after spinal nerve ligation (SNL). Here, we further investigated the effects of the AQP4 and Akt pathways in the spinal dorsal horn (SDH) on the pathogenesis of neuropathic pain (NP). Spinal AQP4 was significantly upregulated after SNL and was primarily expressed in astrocytes in the SDH. Inhibition of AQP4 with TGN-020 attenuated the development and maintenance of NP by inhibiting glial activation and anti-neuroinflammatory mechanisms. Moreover, inhibition of AQP4 suppressed astrocyte activation both in the SDH and in primary cultures.Similar to AQP4, we found that p-Akt was also significantly elevated after SNL. Inhibition of Akt with MK2206 suppressed AQP4 upregulation and astrocyte activation both in vivo and in vitro. Furthermore, Akt blockade with MK2206 alleviated neuropathic pain in the early and late phases after SNL. These results elucidate the mechanisms involved in the roles of Akt/Aquaporin-4 signaling in the development and maintenance of NP. AQP4 is likely to be a novel therapeutic target for neuropathic pain management.
Learn More >Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na1.8 or Advillin neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.
Learn More >Chronic lower back pain is a common report in the general population. A dysfunctional sacroiliac joint (SIJ) is estimated to be responsible for one in five patients with lower back pain. Minimally invasive sacroiliac joint fusion (MISJF) is a surgical procedure to treat SIJ dysfunction. During the procedure, the SIJ is stabilised by implants inserted percutaneously under fluoroscopy guidance. Postoperatively, patients often report a lot of pain, which contributes to patients taking high doses of painkillers (opioids for example,) and preventing early mobilisation. In several orthopaedic procedures, intraoperative infiltration of the wound bed results in decreased consumption of analgesics, earlier mobilisation and shorter hospitalisation time. The aim of this study is to investigate the effectiveness of intraoperative SIJ infiltration with analgesia in reducing postoperative pain after MISJF.
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