Articles: hyperalgesia.
-
Many chronic pain disorders alternate between bouts of pain and periods of remission. The latent sensitization model reproduces this in rodents by showing that the apparent recovery ("remission") from inflammatory or neuropathic pain can be reversed by opioid antagonists. Therefore, this remission represents an opioid receptor-mediated suppression of a sustained hyperalgesic state. To identify the receptors involved, we induced latent sensitization in mice and rats by injecting complete Freund's adjuvant (CFA) in the hindpaw. In WT mice, responses to mechanical stimulation returned to baseline 3 weeks after CFA. In μ-opioid receptor (MOR) knock-out (KO) mice, responses did not return to baseline but partially recovered from peak hyperalgesia. Antagonists of α2A-adrenergic and δ-opioid receptors reinstated hyperalgesia in WT mice and abolished the partial recovery from hyperalgesia in MOR KO mice. In rats, antagonists of α2A adrenergic and μ-, δ-, and κ-opioid receptors reinstated hyperalgesia during remission from CFA-induced hyperalgesia. Therefore, these four receptors suppress hyperalgesia in latent sensitization. We further demonstrated that suppression of hyperalgesia by MORs was due to their constitutive activity because of the following: (1) CFA-induced hyperalgesia was reinstated by the MOR inverse agonist naltrexone (NTX), but not by its neutral antagonist 6β-naltrexol; (2) pro-enkephalin, pro-opiomelanocortin, and pro-dynorphin KO mice showed recovery from hyperalgesia and reinstatement by NTX; (3) there was no MOR internalization during remission; (4) MORs immunoprecipitated from the spinal cord during remission had increased Ser(375) phosphorylation; and (5) electrophysiology recordings from dorsal root ganglion neurons collected during remission showed constitutive MOR inhibition of calcium channels. ⋯ Chronic pain causes extreme suffering to millions of people, but its mechanisms remain to be unraveled. Latent sensitization is a phenomenon studied in rodents that has many key features of chronic pain: it is initiated by a variety of noxious stimuli, has indefinite duration, and pain appears in episodes that can be triggered by stress. Here, we show that, during latent sensitization, there is a sustained state of pain hypersensitivity that is continuously suppressed by the activation of μ-, δ-, and κ-opioid receptors and by adrenergic α2A receptors in the spinal cord. Furthermore, we show that the activation of μ-opioid receptors is not due to the release of endogenous opioids, but rather to its ligand-independent constitutive activity.
-
Nerve growth factor (NGF) plays a pivotal role in survival, growth, and differentiation of the nervous system. Increased levels of NGF have been reported in human pain disorders. Experimental injection of NGF in humans is known to evoke long-lasting mechanical sensitization and subsequent allodynia and hyperalgesia. ⋯ Intradermal NGF injection is capable of inducing reproducible allodynia and hyperalgesia, and the model is recommended for future experimental and pharmacological pain studies.
-
The use of rodents in preclinical studies has contributed greatly to our understanding of the pathophysiology of chronic neuropathic pain. These animal models are limited because of their poor clinical translation. We developed a pig model for chronic pain caused by surgically induced peripheral neuritis trauma (PNT). Seventy-five percent of the animals exhibited mechanical and tactile allodynia, which are indicative of painful neuropathy, by day 28 after surgery. Importantly, the PNT-injured pigs retained their ability to walk or to stand on their injured leg. Messenger RNA analysis of acute inflammatory cytokines calcitonin gene-related peptide and brain-derived neurotrophic factor at the site of injury suggests transient inflammation followed by a persistent high level of neurologic markers. Gabapentin and morphine effectively inhibited hypersensitivity to von Frey filaments and to feather stimuli, and reversed spontaneous pain-related behavior in a dose-related manner. No analgesic effect was detected in PNT-injured pigs after treatment with aprepitant, similar to observations in humans and contrary to observations in rodents. In conclusion, PNT-induced trauma in pigs may comprise a valid preclinical model for the study of the chronification of peripheral nerve injury and for the study of new pain therapies. ⋯ This article presents the characterization of a new peripheral neuritis trauma (PNT) model in pigs. The pig PNT model could help close the translational gap between preclinical and clinical responses and may contribute to improved efficacy or safety of candidate drugs.
-
The diagnostic criteria for primary stabbing headache (PSH) in the 3rd beta edition of International Classification of Headache Disorders (ICDH-3 beta) were recently revised. In the ICDH-3 beta, PSH is defined as short-lasting head pain spontaneous occurring as a single stab or series of stabs without autonomic symptoms and involving all head areas (i.e., not limited to the ophthalmic branch region of the trigeminal nerve). The aim of this study was to investigate the validity of the ICHD-3 beta criteria for PSH in a clinic-based setting. ⋯ All patients with headache with stabbing pain without cranial autonomic symptoms fulfilled the diagnostic criteria for PSH according to ICHD-3 beta at the initial visit. Secondary causes for headache with stabbing pain were revealed in a small proportion (3.7 %) of patients after 2 weeks of follow-up.
-
Fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain and somatic hyperalgesia from central sensitization, is very often comorbid with visceral pain conditions. In fibromyalgia patients with gallbladder calculosis, this study assessed the short and long-term impact of laparoscopic cholecystectomy on fibromyalgia pain symptoms. Fibromyalgia pain (VAS scale) and pain thresholds in tender points and control areas (skin, subcutis and muscle) were evaluated 1week before (basis) and 1week, 1,3,6 and 12months after laparoscopic cholecystectomy in fibromyalgia patients with symptomatic calculosis (n = 31) vs calculosis patients without fibromyalgia (n. 26) and at comparable time points in fibromyalgia patients not undergoing cholecystectomy, with symptomatic (n = 27) and asymptomatic (n = 28) calculosis, and no calculosis (n = 30). ⋯ Over the same 12-month period: in non-fibromyalgia patients undergoing cholecystectomy thresholds did not change; in all other fibromyalgia groups not undergoing cholecystectomy fibromyalgia pain and thresholds remained stable, except in fibromyalgia+symptomatic calculosis at 12months when pain significantly increased and muscle thresholds significantly decreased (p<0.05-p<0.0001). The results of the study show that biliary colics from gallbladder calculosis represent an exacerbating factor for fibromyalgia symptoms and that laparoscopic cholecystectomy produces only a transitory worsening of these symptoms, largely compensated by the long-term improvement/desensitization due to gallbladder removal. This study provides new insights into the role of visceral pain comorbidities and the effects of their treatment on fibromyalgia pain/hypersensitivity.