Resiniferatoxin (RTX) Causes a Uniquely Protracted Musculoskeletal Hyperalgesia in Mice by Activation of TRPV1 Receptors

Inactivation of transient receptor potential vanilloid-1 (TRPV1) receptors is one approach to analgesic drug development. However, TRPV1 receptors exert different effects on each modality of pain. Because muscle pain is clinically important, we compared the effect of TRPV1 ligands on musculoskeletal nociception to that on thermal and tactile nociception. Injected parenterally, capsaicin had no effect on von Frey fiber responses (tactile) but induced a transient hypothermia and hyperalgesia in both the tail flick (thermal) and grip force (musculoskeletal) assays, presumably by its agonistic action at TRPV1 sites. In contrast, resiniferatoxin (RTX) produced a chronic (>58 days) thermal antinociception, consistent with its reported ability to desensitize TRPV1 sites. In the same mice, RTX produced a transient hypothermia (7 hours) and a protracted (28-day) musculoskeletal hyperalgesia in spite of a 35.5% reduction in TRPV1 receptor immunoreactivity in muscle afferents. Once musculoskeletal hyperalgesia subsided, mice were tolerant to the hyperalgesic effects of either capsaicin or RTX whereas tolerance to hypothermia did not develop until after 3 injections. Musculoskeletal hyperalgesia was prevented but not reversed by SB-366791, a TRPV1 antagonist, indicating that TRPV1 receptors initiate but do not maintain hyperalgesia. Injected intrathecally, RTX produced only a brief musculoskeletal hyperalgesia (2 days), after which mice were tolerant to this effect.     

Somatosensory changes in the referred pain area before and after cholecystectomy in patients with uncomplicated gallstone disease

Objective. It is estimated that 25–40% of patients have continuing symptoms after cholecystectomy and that 5–10% have pain. The pain may be related to central neuroplastic changes of sensory pathways induced by the gallstone disease. Such neuronal hyperexcitability can be reflected in the somatic referred pain area sharing central pathways with the gallbladder. The aim of this study was to examine somatosensory changes in the referred pain area evoked by painful gallstone attacks before and after cholecystectomy in patients with uncomplicated gallstone disease. Material and methods. Thirty-seven patients with uncomplicated gallstone disease were included in the study. The sensations and pain thresholds to pinprick, pinching, pressure, thermal and electrical stimulation were studied before and 4–12 weeks after surgery in the area where the pain was referred to during the previous gallstone attacks. An area on the contralateral side of the abdomen served as the control. Results. Somatosensory hyperalgesia in the referred pain area was observed in 84% of the patients before surgery. After elective cholecystectomy, none of the patients had pain complaints, and the sensibility in the referred area was normalized. Conclusions. Uncomplicated gallstone disease leads to significant hyperalgesia in the somatic referred pain area. At the time of the postoperative investigation none of the patients suffered from pain, which was reflected in the normal sensory findings in the previous referred pain area.     

Induction of long‐term potentiation at spinal synapses by noxious stimulation or nerve injury

Use-dependent long-term potentiation of synaptic strength (LTP) is an intensively studied model for learning and memory in vertebrates. Induction of LTP critically depends on the stimulation parameters of presynaptic fibres with synchronous high-frequency bursts being most effective at many central synapses. It is, however, not known whether naturally occurring discharge patterns may induce LTP and whether LTP has any biological function in sensory systems. Here we have investigated the LTP of excitatory synaptic transmission between primary afferent C-fibres, many of which are nociceptors, and neurons in rat superficial spinal dorsal horn. LTP that lasted for 4–6 h could not only be induced by electrical stimulation of sural nerve but also by natural stimulation of heat-, mechano- or chemosensitive nociceptors in the skin or by acute nerve injury. Maintenance of LTP was not affected when afferent nerves were cut 1 h or 5 min after noxious skin stimulation, indicating that an ongoing afferent barrage is not required. Natural noxious stimuli induced LTP in animals which were spinalized but were ineffective in intact animals. Thus, induction of LTP is suppressed by tonically active supraspinal descending systems. We conclude that the natural non-synchronized discharge patterns that are evoked by noxious stimulation may induce LTP and that this new form of LTP may be an underlying mechanism of afferent induced hyperalgesia.     

Neonatal gastric suctioning results in chronic visceral and somatic hyperalgesia: role of corticotropin releasing factor

Abstract Gastric suctioning is common in neonatal intensive care units. Studies suggest that gastric suctioning in premature infants may play a role in the development of visceral hyperalgesia. We hypothesized that repeated orogastric suctioning during the neonatal period results in chronic alterations in visceral and somatic sensation through a corticotropin-releasing factor mediated mechanism. Neonatal male Long Evans rats (n = 13) received daily orogastric suctioning for 10 days starting at postnatal day two (P2). Control rats (n = 15) were handled similarly without orogastric suction. A second study group was subjected to a similar protocol, only with pre-emptive administration of a CRF1 receptor antagonist (antalarmin, 20 mg/kg, IP) (n = 8). The control group received vehicle only (n = 8). An additional group was given antalarmin without suctioning (n = 5). After these rats grew to adulthood (PN 60), a visceromotor response to graded colorectal distension was recorded (10-80 mmHg, 30s, 180s inter-stimulus intervals) to assess changes in visceral sensitivity. Paw withdrawal latency to noxious heat applied to the hind paws was measured to assess changes in cutaneous sensitivity. Orogastric suctioning during the neonatal period results in global chronic somatic and visceral hyperalgesia in adult rats. Visceral hyperalgesia is prevented by pre-emptive administration of the CRF1 receptor antagonist, antalarmin.     

Long-term outcome following sympathectomy for complex regional pain syndrome type 1 (RSD)

We performed a retrospective study of 29 patients with CRPS1 (RSD) who were initially examined between 1983 and 1993, and had either transthoracic (lower third of stellate ganglia to T3) or lumbar (L2–L4) sympathectomy. The patients were followed from 24 to 108 months after surgery. Patients with unsuccessful surgical outcomes had significantly longer duration of symptoms before surgery (median, 36 months) than those with successful outcomes (median, 16 months) by Wilcoxon rank sum test (χ²=8.69, df=1, P<0.01). All seven patients (100%) who had sympathectomy within 12 months of injury, nine of 13 patients (69.2%) who had sympathectomy within 24 months of injury, and only four of nine patients (44.4%) who had sympathectomy after 24 months of injury obtained permanent (greater than 24 months) symptom relief. Patient age, sex, occupation, site of injury, type of injury, presence of trophic changes, and duration of follow-up were not significantly related (P>0.05) to surgical outcome.     

IS FLEMING'S LYSOZYME AN ANALGESIC AGENT? EXPERIMENTS ON MICE

1. Antinociceptive activity of hen egg white lysozyme (Fleming's lysozyme) was determined against abdominal contractions provoked by irritants injected intraperitoneally into mice. Carrageenan (2 mg) (CA) injected with arachidonic acid (15 micrograms) (AA) or prostaglandins PGE1 or PGF2 alpha (0.04 ng), brewer's yeast (10 mg), caolin (10 mg), mepartricin (80 U) and phenylquinone (50 micrograms) were used as irritants. 2. Lysozyme was active at 400-800 mg/kg i.v. against CA + AA, CA + PG, brewer's yeast and caolin nociceptive stimulation. The compound was more effective against CA + AA than against CA + PG. Acetylsalicylic acid at 50-100-200 mg/kg p.o. was equally active against CA + AA and CA + PG. 3. Lysozyme was inactive in the tail pinch and hot plate tests that mainly detect central analgesics. 4. The results are discussed in relation to the claim advanced years ago that lysozyme is an effective analgesic agent in humans. The compound was found active against herpes zoster or cancer pain but did not find use despite the favourable reports presented. 5. The experimental results obtained on laboratory animals do not contradict the conclusions drawn after the clinical use of the compound.     

Experimental evaluation of the analgesic effect of ibuprofen on primary and secondary hyperalgesia

The analgesic effect of systemic ibuprofen was investigated with two human experimental pain models: (i) static mechanical stimulation of the inter digital web between the 2nd and 3rd finger and (ii) primary and secondary hyperalgesia induced by a 7-min burn injury on the calf. In each double-blind, randomized, two-way cross-over study 20 healthy male volunteers received either ibuprofen 600 mg or placebo tablets. Ibuprofen reduced pain evoked by static mechanical pressure in normal skin and by motor brush stimulation in the area of secondary hyperalgesia following burn injury. In contrast, ibuprofen did not reduce the area of secondary hyperalgesia to either pinprick or stroke following burn injury. Previous human experimental studies concerning the analgesic effect of NSAIDs are reviewed. Based on the previous literature and the present results we suggest that NSAIDs inhibit progressive tactile hypersensitivity but not the central sensitization itself.     

Hyperalgesia mediated by peripheral opiate receptors in the rat

Behavioural experiments were undertaken to investigate the possible functional significance of opiate receptors located at peripheral endings of primary sensory neurons. The responses of animals to noxious chemical stimuli applied to the ear (ear scratch test) were measured after local pretreatment of these areas with etorphine. Local etorphine administration produced a low dose hyperalgesia and high dose analgesia. Local as opposed to systemic effects of etorphine were inferred from the absence of effects on the contralateral vehicle-treated ear. Systemic administration of naloxone or of a quaternary opiate antagonist (MRZ 2663-BR), which is relatively ineffective in crossing the blood-brain barrier, blocked the low dose hyperalgesic effect of etorphine in the ear scratch test. As a test for the putative hyperalgesic function of peripheral sensory nerve opiate receptors, neonatal rats were treated with capsaicin (50 mg/kg s.c.) to destroy specifically the subpopulation of primary sensory neurons on which the peripheral opiate receptors are thought to be located, without markedly altering pain thresholds. As adults, these neonatally treated rats showed potentiated analgesic responses to systemic morphine, as would be predicted by central ‘analgesic’ opiate receptors now acting without opposition from peripheral ‘hyperalgesic’ opiate receptors. These findings suggest that opiate receptors on primary sensory neurons may mediate hyperalgesic functions and that endogenous opioids might normally play a role in the peripheral induction of irritation, inflammation and pain reactions.     

Symptoms and visceral perception in severe functional and organic dyspepsia

^a CURE: Digestive Disease Research Center/Neuroenteric Disease Program, UCLA, Los Angeles, California, USA, ^b Department of Medicine, Vanderbilt University, Nashville, Tennessee

Correspondence to: Dr E A Mayer, Neuroenteric Disease Program, West LA VA Medical Center, CURE Bldg 115, Rm 223, 11301 Wilshire Blvd, Los Angeles, California 90073, USA.

Accepted for publication 31 October 1997

Background—Hypersensitivity of gastric afferent pathways may play an aetiological role in symptoms of functional dyspepsia.
Aims—To determine whether patients with severe organic dyspepsia (associated with tissue irritation/injury) and those with functional dyspepsia (no detectable tissue irritation) differ in their perception of gastric distension and whether this difference is reflected in differences in their gastrointestinal and psychological symptoms.
Methods—Perceptual thresholds, referral patterns, and gastrointestinal and psychological symptoms were compared in 23 patients with functional dyspepsia, 10 organic dyspeptics, and 15 healthy controls.
Results—Fifteen (65%) functional dyspeptics and no organic dyspeptics had reduced perceptual thresholds for fullness, discomfort, or pain (odds ratio (OR) 19.56, 95% confidence interval (CI) 1.95 to 476.09, p=0.0017). Either reduced perceptual thresholds or altered referral was found in 20 (87%) functional dyspeptics and four (20%) organic dyspeptics (OR 10.0, 95% CI 1.34 to 89.54, p=0.014). During sham distension fullness, discomfort and pain were reported by healthy controls, organic dyspeptics, and functional dyspeptics. A sham response of pain but no other sensation was more frequent among functional dyspeptics (43%) than healthy controls (7%) (OR 10.77, 95% CI 1.10 to 257.35, p=0.026). Gastrointestinal and psychological symptoms and gastric compliance were similar in the functional and organic groups.
Conclusions—Alterations in the perception of gastric distension distinguishes between functional and organic dyspepsia, while symptoms do not. A total of 87% of functional dyspeptics studied had evidence of altered visceral afferent function. In this study population, psychological abnormalities or changes in compliance did not explain the findings.
(GUT 1998;:814-822)

Keywords: dyspepsia;  hyperalgesia;  visceral afferents