Pain
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Urinary bladder pain is a primary symptom associated with interstitial cystitis/painful bladder syndrome. We used systemic injections of cyclophosphamide (CYP), an alkylating antineoplastic agent, to induce cystitis and examine the roles of 2 channels previously demonstrated to be required for inflammatory visceral hyperalgesia: transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1). Injection of CYP (100 mg/kg, i.p.) every other day for 5 days was accompanied by bladder edema and urothelial ulceration, but without significant plasma extravasation or infiltration of neutrophils. ⋯ Moreover, bladder hyperalgesia was reversed by acute treatment with the TRPA1 antagonist HC-030031 (300 mg/kg, i.p.). Our results indicate that CYP-induced bladder hyperalgesia can be induced without robust inflammation or changes in primary afferent TRPV1. However, significant changes were observed in TRPA1 expression, and blockade of TRPA1 alleviated CYP-induced bladder hyperalgesia.
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Nociceptive signaling from the meninges is proposed to contribute to many forms of headache. However, the events within the meninges that drive afferent activity are not clear. Meningeal fibroblasts are traditionally thought to produce extracellular proteins that constitute the meninges but not to contribute to headache. ⋯ Finally, stimulation of cultured fibroblasts with LPS increased IL-6 levels in the media. These findings demonstrate that fibroblasts stimulated with LPS release factors capable of activating/sensitizing dural afferents. Further, they suggest that fibroblasts play a potential role in the pathophysiology of headache.
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Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2- and β3-adrenergic receptors (β2ARs and β3ARs). Here we investigated molecules downstream of β2- and β3ARs driving pain in animals with decreased COMT activity. ⋯ Finally, we found that NO influences TNFα, IL-1β, IL-6, and CCL2 levels, whereas TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2- and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2- and β3ARs, NO, and proinflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.
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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. ⋯ PAR2 signaling in dorsal root ganglia led to extracellular signal-regulated kinase (ERK)1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS.
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Empathy for the pain experience of others can lead to the activation of pain-related brain areas and can even induce aberrant responses to pain in human observers. Recent evidence shows this high-level emotional and cognitive process also exists in lower animals; however, the mechanisms underlying this phenomenon remain unknown. In the present study we found that, after social interaction with a rat that had received subcutaneous injection of bee venom (BV), only the cagemate observer (CO) but not the noncagemate observer (NCO) showed bilateral mechanical hypersensitivity and an enhanced paw flinch reflex following BV injection. ⋯ Anxiety can also be excluded because anxiety-like behaviors could be seen in both the CO and NCO rats tested in the open-field test. Finally, bilateral lesions of the medial prefrontal cortex eliminated the enhancement of the BV-induced paw flinch reflex in CO rats, but bilateral lesions of either the amygdala or the entorhinal cortex failed. Together, we have provided another line of evidence for the existence of familiarity-dependent empathy for pain in rats and have demonstrated that the medial prefrontal cortex plays a critical role in processing the empathy-related enhancement of spinal nociception.