Evidence for a novel, neurohumoral antinociceptive mechanism mediated by peripheral capsaicin-sensitive nociceptors in conscious rats (original) (raw)
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European Journal of Pharmacology, 2009
The behavioural noxious heat threshold i.e. the lowest temperature evoking nocifensive behaviour was previously shown to decrease in short-lasting, but not in sustained, inflammatory thermal hyperalgesias. The aim of this study was to examine whether the surgical incision-induced lasting heat hyperalgesia involves a drop of the heat threshold and to assess the effects of conventional opioid and non-opioid analgesics in this model. One of the hind paws of rats was immersed into a water bath whose temperature was near-linearly increased from 30°C until the animal withdrew its paw from the water. The corresponding bath temperature was considered as the behavioural noxious heat threshold. Hyperalgesia to heat was induced by a standardized plantar surgical incision performed under pentobarbital anaesthesia which led to a 5−7°C decrease of the noxious heat threshold for seven days. Morphine, diclofenac, and paracetamol administered intraperitoneally 18 h after incision dose-dependently inhibited the drop of heat threshold with minimum effective doses of 0.3, 1, and 100 mg/kg, respectively, as assessed 20, 30 and 40 min after treatment. Thermal hyperalgesia was also decreased by intraplantar treatment with morphine (10 µg) or diclofenac (100 μg). In conclusion, the incision-induced sustained thermal hyperalgesia in rats involves a drop of the heat threshold suggesting that mechanisms of postsurgical pain are distinct from those of pure inflammatory pain. The thermal antihyperalgesic actions of systemically and/or locally applied morphine, diclofenac and paracetamol could be detected with high temporal resolution and sensitivity in this model.
Neuroscience, 2006
Intradermal capsaicin injection produces immediate spontaneous pain behaviors, and a secondary mechanical hypersensitivity (SMH) that is employed in the clinic as a model potentially predictive of human neuropathic pain. Presently, we have characterized capsaicin-induced SMH in rats, and compared pharmacological actions of standard analgesics in this and two nerve injury models, the L5/L6 spinal nerve ligation (SNL) and sciatic nerve chronic constriction injury (CCI) models. Intraplantar capsaicin produced doserelated SMH (enhanced paw withdrawal response to von Frey monofilament stimulation at an area away from injection site) that lasted for over 4 h. While pretreatment with a potent selective transient receptor potential vanilloid receptor-1 (TRPV1) antagonist A-425619 (1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea) prevented development of acute nocifensive (flinching) behavior immediately following capsaicin injection (ED 50 9.4؍ mg/kg), the compound failed to attenuate the SMH when administered 2 h following capsaicin (10 g/10 l). Additional standard analgesics were also tested 3 h following intraplantar capsaicin in the SMH model. Comparison of their potencies in attenuating mechanical hypersensitivity in capsaicin, SNL and CCI models revealed similar ED 50 s for morphine (2.3 mg/kg, 1.6 mg/kg and 3.2 mg/ kg, respectively), gabapentin (33.1 mg/kg, 33.9 mg/kg and 26.3 mg/kg, respectively) and lamotrigine (9.1 mg/kg, 8.9 mg/kg and 15.5 mg/kg, respectively). Duloxetine produced 50-65% effect at the highest tested dose (50 mg/kg), whereas the highest tested doses of morphine (10 mg/kg), gabapentin (85.5 mg/kg) and lamotrigine (30 mg/kg) all produced >70% efficacy in capsaicin SMH, SNL and CCI models. In contrast, celecoxib and ibuprofen showed weak effects in all three models. All standard analgesics generally had weak efficacy in attenuating capsaicin-induced immediate acute flinching behavior when administered before capsaicin. These results provide further support to the suggestions that distinct pharmacological mechanisms underlie capsaicin-induced acute nocifensive and SMH behaviors, and certain neuronal mechanisms underlying neuropathic pain states are also contributory to capsaicin-induced SMH.
Anesthesiology, 2008
Background-Transient receptor potential vanilloid 1 channels integrate nociceptive stimuli and are predominantly expressed by unmyelinated C-fiber nociceptors, but not low-threshold mechanoreceptive sensory or motor fibers. A recent report showed that the transient receptor potential vanilloid 1 channel agonist capsaicin allows a hydrophilic quaternary ammonium derivative of lidocaine, QX-314, to selectively block C fibers without motor block. The authors tested whether a similar differential block would be produced using amphipathicN-methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, either alone or together with 0.05% capsaicin, in a rat sciatic nerve block model.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1990
The effects of capsaicin pretreatment of adult rats was investigated on consequences of unilateral paw inflammation induced by inoculation with Freund's adjuvant. Decrease in mechanical nociceptive threshold in the inflamed paw, as measured by the paw pressure test, was dose-dependently inhibited by capsaicin (20-150 mg/kg s.c.). In control rats, the antinociceptive action of morphine (0.8-1.9 mg/kg s.c.) was greater in the inflamed than in the non-inflamed paw; this difference was absent in capsaicin-treated animals. Increased volume or skin temperature of the inflamed paw was not influenced by capsaicin. It is concluded that capsaicin-sensitive, presumably C-fibre neurones, but not an alteration of the inflammation itself by capsaicin, mediate hyperalgesia and increased morphine antinociception in the rat paw with adjuvant-induced inflammation.
European Journal of Pharmacology, 2000
The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In Ž . atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres 8 Hz, 20 min, at C-fibre strength inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45 " 3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46 " 5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function. q
Opioidergic activation in the medial pain system after heat pain
PAIN, 2006
Opioids modulate the affective component of pain and in vivo data indicate that opioids induce activation changes in the rostral ACC, insula and other brain areas. Hence, opioidergic release is to be expected in these brain regions following experimental pain stimulation. We examined healthy volunteers during heat pain and control subjects during rest using [18F]fluorodiprenorphine-PET. Pain stimulation led to significant reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula. The finding of altered opioidergic receptor availability in the rostral ACC after experimental nociceptive pain is novel and provides direct evidence for the involvement of this region in endogenous opioidergic inhibition of pain. Ó
Pain, 1995
Intradermal injection of the capsaicin analogue, NE-21610 (Procter and Gamble), inactivates nociceptors but not low-threshold mechanoreceptors in monkey. The present study examined the effects of cutaneous NE-21610 on heat and mechanical sensation in normal human volunteers. In the first series of experiments, subjects received intradermal (i.d.) injections (30 microliters) of the vehicle alone or with the drug (0.3, 3.0, 10 micrograms) into different sites on the volar forearm. Subjects were randomly assigned to 1 of 3 protocols to examine drug-evoked pain (n = 8), or alterations in pain to heat (n = 8) or mechanical (n = 8) stimuli induced by the drug. An additional 7 subjects rated pain to mechanical and heat stimuli before and after subcutaneous (s.c.) injections (300 microliters) of the vehicle or drug (100 micrograms). The peak pain occurred at the time of injection, was of short duration, and was similar for vehicle and drug injections. A mild, dose-related pain followed that...
A model of transient hyperalgesia in the behaving monkey induced by topical application of capsaicin
Pain, 1997
The aim of this study was to develop a model of transient hyperalgesia in the awake monkey performing operant tasks. An adult male rhesus monkey was trained to press a lever to receive food reward for detecting a light or to escape mechanical or thermal stimuli applied in the maxillary region of the face. A small contact thermode was positioned on one side of the face and a mechanical stimulator was placed on the other side. Noxious and innocuous thermal (43, 47 and 51°C) or mechanical (245, 490, 736 and 1472 mN) stimuli of 4.5-s duration were presented in a pseudo-random order. The animal was tested before, 1 h and 24 h after topical capsaicin application (0.3 ml; 0.004 M). At the site of capsaicin application, the monkey escaped more thermal and mechanical stimuli 1 h after than before capsaicin, suggestive of thermal and mechanical hyperalgesia. At 24 h post-capsaicin, mechanical escape behavior had returned to baseline, but thermal escapes were still slightly elevated. Capsaicin had no significant effect on either mechanical or thermal escape behavior for stimuli presented to the contralateral site. Seven human subjects tested with these procedures reported higher pain intensity for similar stimuli after capsaicin application, in accordance with the monkey escape behavior. It is concluded that topical application of capsaicin on the maxillary face of the awake behaving monkey produces a transient thermal and mechanical hyperalgesia. The procedure is repeatable and produces no overt signs of distress. Thus it could provide an important tool for studying neural mechanisms of hyperalgesia and for testing analgesic treatments in primates.