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PubMed1996

Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil.

The present series of experiments were designed to examine a potential role for central descending pain facilitatory systems in mediating secondary hyperalgesia produced by topical application of mustard oil and measuring the nociceptive tail-flick reflex in awake rats. Topical application of mustard oil (100%) to the lateral surface of the hind leg produced a facilitation of the tail-flick reflex that was significantly reduced in spinal transected animals. Mustard oil hyperalgesia was also inhibited in animals that had received electrolytic lesions in the rostral ventromedial medulla (RVM). Intrathecal (i.t.) administration of the non-selective cholecystokinin (CCK) receptor antagonist proglumide (10 micrograms) prior to mustard oil application completely blocked both the lesser and greater hyperalgesic responses observed in spinal transected and normal animals, respectively, and produced an inhibition of the tail-flick reflex in normal animals. Administration of the selective CCKB receptor antagonist L-365260 i.t. dose-dependently inhibited mustard oil hyperalgesia (ID50 = 364 ng) at doses approximately 5-fold less than the CCKA receptor antagonist devazepide (ID50 = 1760 ng). Similar to spinal proglumide, microinjection of the neurotensin antagonist SR48692 (3.5 micrograms) into the RVM blocked mustard oil hyperalgesia and inhibited the tail-flick reflex. These data suggest that secondary hyperalgesia produced by mustard oil is mediated largely by a central, centrifugal descending pain facilitatory system which involves neurotensin in the RVM and spinal CCK (via CCKB receptors). The inhibition of the tail-flick reflex produced by mustard oil following spinal or supraspinal administration of receptor antagonists suggests concurrent activation of central descending facilitatory and inhibitory systems.

Animals↗
PubMed1985

Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia.

Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.) than oedema (180 mg/kg, i.p.) Dipyrone administered intraperitonially or intraplantarly was able to antagonise PGE2-, isoprenaline- and calcium chloride-induced hyperalgesia, effects which are not observed with non-steroid anti-inflammatory drugs. Systemic or local administration of dipyrone had no effect upon Db-cAMP-induced hyperalgesia while a centrally acting analgesic, morphine, given systemically, was highly effective. These results support our suggestion that the mechanism of action of dipyrone is different from that of classical non-steroidal anti-inflammatory drugs. Although the site of action is peripheral its analgesic effect does not derive from inhibition of the synthesis of prostaglandins but is exerted via direct blockade of the inflammatory hyperalgesia.

Acetaminophen↗
PubMed1987

A peripheral sympathetic component in inflammatory hyperalgesia.

Non-steroidal anti-inflammatory drugs (NSAID) only partially inhibit the hyperalgesia in the inflammation induced by carrageenin in the hind rat paw, one of the most frequently used nociceptive tests. We now report that either the guanethidine depletion of peripheral sympathomimetic amines or the treatment with adrenoceptor antagonists (beta-blockers) and a specific dopamine (DA)-1 antagonist (SCH 23390) significantly reduced carrageenin hyperalgesia. These antagonists also abolished the rat paw hyperalgesia induced by several sympathomimetic amines as well as that induced by a selective DA-1 agonist, SKF 38393. Blockade of uptake-1 by cocaine potentiated the hyperalgesia induced by carrageenin and sympathomimetic amines. We conclude that there is a sympathetic component, possibly mediated by a DA-1 type receptor in carrageenin-induced hyperalgesia. This component may predominate in certain types of pain not sensitive to NSAID. If so, selective peripheral DA-1 antagonists could be developed as a novel class of analgesics.

Adrenergic beta-Antagonists↗
PubMed1994

Intrathecal injection of cell-permeable analogs of cyclic 3',5'-guanosine monophosphate produces hyperalgesia in mice.

Several recent studies suggest that spinal cord levels of cyclic 3',5'-guanosine monophosphate (cGMP) may participate in the development of hyperalgesia. The purpose of this study was to directly evaluate whether cell permeable analogues of cGMP evoke a thermal hyperalgesia (using a hot-plate assay) when administered intrathecally in mice. Our results indicate that two cell permeable forms of cGMP evoke a dose dependent hyperalgesia when administered intrathecally in mice. Additionally, this hyperalgesia was selective since neither non-cell permeant cGMP nor guanosine had any effect on the latency of paw withdrawal when compared to the vehicle injected controls. These data indicate that cGMP is involved in the facilitation of thermal hyperalgesia at the level of the spinal cord.

Animals↗
PubMed1995

Influence of selective alpha 2-adrenergic agents on mustard oil-induced central hyperalgesia in rats.

The effects of systemically administered medetomidine, an alpha 2-adrenoceptor agonist, and atipamezole, an alpha 2-adrenoceptor antagonist, on mustard oil-induced central hyperalgesia were determined in unanesthetized rats. The mechanical threshold for eliciting a hindlimb flexion reflex (a nocifensive response) was determined with a series of calibrated monofilaments. Under control conditions mustard oil produced a significant decrease of the hindlimb withdrawal threshold for mechanical stimuli applied to a distal site in the hindlimb, whereas the corresponding threshold in the (untreated) contralateral side was not changed. Medetomidine administered 12 min prior to mustard oil treatment produced a significant dose-dependent (3-30 micrograms/kg s.c.) attenuation of the mustard oil-induced threshold decrease whereas the withdrawal threshold of the contralateral (untreated) hindlimb was not changed at these low doses. The antinociceptive effect of medetomidine (10 micrograms/kg) administered 12 min prior to the mustard oil treatment was not significantly stronger than the effect of medetomidine administered immediately after the mustard oil treatment. Atipamezole at a high (1000 micrograms/kg) or a low (10 micrograms/kg) dose did not influence the mustard oil-induced threshold decrease, whereas at an intermediate dose (100 micrograms/kg) atipamezole alone had a significant antinociceptive effect on mustard oil-induced hyperalgesia. The results indicate that medetomidine produces a selective attenuation of central hyperalgesia at doses which are sub-antinociceptive in intact rats. A pre-emptive treatment with medetomidine did not produce stronger antinociception than medetomidine treatment after the development of hyperalgesia. An alpha 2-adrenoceptor antagonist, atipamezole, attenuated central hyperalgesia in a non-monotonic fashion.

Adrenergic alpha-Agonists↗
PubMed1989

Naloxone-sensitive hyperalgesia follows analgesia induced by morphine and environmental stimulation.

Manipulations of attack parameters in murine agonistic encounters have shown that moderate attack terminating at the first unambiguous display of the upright submissive posture results in nonopioid analgesia. By contrast, attack continuing significantly beyond this behavioural marker results in decreases in nociception mediated by opiodergic mechanisms. However, these effects have only been demonstrated immediately upon termination of encounters. As such, little is known of the influences of agonistic encounters on nociceptive responding beyond this. Tail-flick latencies of male DBA/2 mice that had been exposed to opioid activating attack parameters were established at 15-minute intervals up to 90 min postattack. Data suggest the existence of at least two distinct phases in nociceptive responding with 1) analgesia being evident in the early phase (0-45 min) and 2) short-lasting (detectable only at 75 min postattack) hyperalgesia in the late phase. Further studies revealed both of these effects to be reversed by low (1-10 mg/kg) doses of naloxone. Interestingly, alterations in responsivity to noxious stimulation postmorphine (1-20 mg/kg) administration followed a similar pattern, with analgesia being detectable 0-2 hr and hyperalgesia being evident at 4 hr postinjection of either 10 or 20 mg/kg morphine. However, only the hyperalgesia induced by 20 mg/kg morphine was reversed by 10 but not 1 mg/kg naloxone. These data together suggest a relationship between the dose of morphine required to induce hyperalgesia and the amount of naloxone needed to reverse this response. The naloxone-reversibility of postencounter or morphine-induced hyperalgesia suggests that these effects are not a consequence of the absence of opiates/opioids per se.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1982

Hyperalgesia induced by non-noxious stress in the rat.

Stress-induced analgesia is well known but the reverse phenomenon is poorly documented. In this work, hyperalgesia is described following stressful but non-noxious manipulations consisting of inescapable holding or exposure to a novel environment. Hypophysectomy (HX) and dexamethasone enhanced 'holding' hyperalgesia. In contrast, 'novelty' hyperalgesia was reduced by HX and not modified by dexamethasone. So, pituitary factors may respectively compensate and take part in stress hyperalgesia. Thus pain can be modulated in opposite directions by different types of stimulation: hyperalgesia would predominate after moderate, anxiogenic stress and analgesia after noxious and/or intense stress.

Animals↗
PubMed1995

Role of peri-axonal inflammation in the development of thermal hyperalgesia and guarding behavior in a rat model of neuropathic pain.

Loose ligation of a rat's sciatic nerve produces hyperalgesia to thermal stimuli and elicits guarding behavior directed at the afflicted paw. The present experiments test whether localized inflammation induced by the suture material used to ligate the nerve is critical to the development of hyperalgesia. Daily injections of dexamethasone reduced the inflammatory response induced by the sutures and blocked the development of guarding behavior and thermal hyperalgesia. In a second experiment inflammation associated with cotton sutures was enhanced by soaking the sutures in Freund's adjuvant prior to ligation. This caused an augmentation of thermal hyperalgesia and guarding behavior. These results suggest that inflammation around the nerve is critical for the development of guarding behavior and thermal hyperalgesia in this model of neuropathic pain.

Animals↗
PubMed1994

Pre treatment with MK-801, a non-competitive NMDA antagonist, prevents development of mechanical hyperalgesia in a rat model of chronic neuropathy, but not in a model of chronic inflammation.

In the rat, loose ligation of the sciatic nerve results in behavioural signs of hyperalgesia reminiscent of neuropathy in man. A further rat model, of chronic inflammatory hyperalgesia, is produced by intraplantar administration of Freund's complete adjuvant (FCA). We report here that preemptive administration of a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, MK-801 (0.3 mg kg-1, s.c.) 30 min prior to and twice daily for a further 8 days following loose ligation of the sciatic nerve, blocks the development of mechanical hyperalgesia measured 27 days later. In contrast, MK-801 administration using the same dosing regimen did not significantly inhibit the hyperalgesia apparent 15 days following i.pl. administration of FCA. Our results suggest that the mechanisms responsible for the development of mechanical hyperalgesia associated with chronic nerve injury and chronic inflammation differ.

Animals↗
PubMed1995

The effect of continuous morphine analgesia on chronic thermal hyperalgesia due to sciatic constriction injury in rats.

We employed hindfoot withdrawal latencies to radiant heat to assess the analgesic effect of prolonged morphine infusion on thermal hyperalgesia induced by chronic constriction injury (CCI) of the rat sciatic nerve. All CCI rats developed thermal hyperalgesia while sham-operated animals did not. Continuous systemic infusion of morphine dose-dependently reversed the thermal hyperalgesia in the CCI rats. In contrast, thermal hyperalgesia persisted in saline-treated CCI rats. Tolerance to morphine's analgesic effect did not develop over a period of seven days of morphine infusion, which is considered long-term for animal models. These data suggest that morphine acts rapidly and effectively to reduce behavioral signs of hyperalgesia in rats with sciatic CCI, without the concomitant development of tolerance. Scheduled administration of morphine might be an appropriate treatment regimen for relief of neuropathic pain, and the infrequent use of opioids in equivalent human clinical pain syndromes due to fear of opioid unresponsiveness and tolerance might need to be re-evaluated.

Analgesia↗
PubMed1996

Application of nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, on injured nerve attenuates neuropathy-induced thermal hyperalgesia in rats.

This study tested the ability of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), to attenuate behavioral hyperalgesia in a rat model of neuropathic pain [Bennett, G.J. and Xie, Y.-K., Pain, 33 (1988) 87-107]. A mononeuropathy was produced by chronic constriction injury (CCI) of the sciatic nerve. Thermal hyperalgesia was assessed by a reduction of paw withdrawal latency to a noxious heat source. Following CCI, there was significant hyperalgesia in groups of rats treated with D-NAME (n = 7), an inactive isomer of L-NAME, saline (n = 7) or systemic L-NAME (n = 10). In contrast, when L-NAME was applied directly and continuously to the site of CCI (5.0 micrograms/microliter per h for up to 2 weeks) via an osmotic pump implanted at the time of the injury, no significant thermal hyperalgesia was observed (n = 8). The results suggest the involvement of nitric oxide in the development and maintenance of thermal hyperalgesia in a rat model of neuropathy. The blockade of nitric oxide production at the site of injury may provide a new approach for treatment of neuropathic pain.

Animals↗
PubMed1988

Myelinated afferents signal the hyperalgesia associated with nerve injury.

Pain to light touching of the skin is a hallmark sign of causalgia. The purpose of this study was to determine whether myelinated or unmyelinated afferent fibers signal this hyperalgesia. Sensory testing was performed in 17 patients with long-standing hyperalgesia after nerve injury. The patients underwent a differential ischemic block of nerve function of the involved area. At a time when touch sensation in adjacent normal skin was eliminated, but when sensibility to warming and cooling stimuli was unaffected, the hyperalgesia to mechanical stimuli was abolished in 15 of the subjects. In 2 of these 15 patients, a differential local anesthetic block of the injured nerve was performed proximal to the site of injury. When temperature sensibility was absent, but when touch sensation was intact, hyperalgesia was present. In a third study, latency measurements in response to 400 micron stepped displacement stimuli were made in two patients who had hyperalgesia on the foot. The mean latency for detection of pain in the hyperalgesic region was 414 +/- 18 msec, compared to 458 +/- 16 msec for the detection of touch to the same stimuli applied to the opposite normal foot. These 3 lines of evidence indicate that myelinated primary afferents, perhaps A beta fibers, signal the hyperalgesic pain in causalgia. These fibers may be sensitized A beta nociceptors or low-threshold mechanoreceptors.

Adult↗
PubMed1992

The effects of a non-competitive NMDA receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation.

The involvement of NMDA receptors in rats with peripheral inflammation and hyperalgesia was evaluated by administration of the non-competitive NMDA receptor antagonist, MK-801. Inflammation and hyperalgesia was induced by intradermal injection of complete Freund's adjuvant (CFA) or carrageenan into the left hind paw. The latency of paw withdrawal from a thermal stimulus was used as a measure of hyperalgesia in awake rats. MK-801 (1.6 mg/kg, i.p., or 31.5 micrograms, intrathecal) significantly attenuated thermal hyperalgesia and reduced its duration in comparison to saline-injected rats (P less than 0.05). The receptive field size of nociceptive-specific and wide-dynamic-range neurons in the superficial and deep spinal dorsal horn recorded 24 h after injection of CFA was significantly reduced to 73 +/- 6% (P less than 0.05, n = 8) and 74 +/- 4% (P less than 0.05, n = 8) of control values, respectively, by a cumulative dose of 3 mg/kg of MK-801 (i.v.). MK-801 (2 mg/kg) prevented the expansion of the receptive fields of dorsal horn neurons recorded 5 +/- 0.4 h (n = 5) after intradermal injection of CFA as compared to saline-injected rats (P less than 0.05). MK-801 had no significant effect on receptive field size of dorsal horn neurons in rats without CFA-induced inflammation but blocked a transient expansion of the receptive fields induced by 1 Hz, C-fiber intensity electrical stimulation of the sciatic nerve. The background activity and noxious heat-evoked response of dorsal horn neurons in rats with CFA-induced inflammation were primarily inhibited and noxious pinch-evoked activity was both facilitated and inhibited by the administration of MK-801. These results support the hypothesis that NMDA receptors are involved in the dorsal horn neuronal plasticity and behavioral hyperalgesia that follows peripheral tissue inflammation.

Animals↗
PubMed1995

Inflammatory models of cutaneous hyperalgesia are sensitive to effects of ibuprofen in man.

A new experimental procedure was developed to quantify the analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs) in healthy human subjects. In order to mimic the clinical situation, the drug was 'therapeutically' administered 1 day after induction of inflammation by freezing a small skin area. The procedure was easily tolerated and led to a marked hyperalgesia without ongoing pain which was tested using mechanical impact stimulation and magnitude estimation. For comparison, we used a previously established model of repeated noxious pinching of an interdigital skin web which induces a hyperalgesia to pressure (rated via visual analogue scale), and topical application of capsaicin which leads to quantifiable flare and allodynia responses. The effects of a cumulative drug regime of ibuprofen in 2 different doses (3 x 400 mg and 3 x 800 mg at 2-h intervals) were tested versus placebo using a double-blind cross-over design with 24 volunteers of either gender. Ibuprofen caused a significant suppression of the hyperalgesia to repeated pinching and of the hyperalgesia to impact stimulation following freeze trauma. In contrast, there was no effect on the areas of flare and allodynia induced by capsaicin application and on the impact evoked sensations from untreated skin. The two dosages of ibuprofen, however, appeared to be equally effective in a way that suggests a plateauing of the antihyperalgesic effect. The two models in which hyperalgesia is affected by ibuprofen, i.e., repeated pinching and impact stimulation after freeze trauma, seem to provide comparable sensitivity. The freeze model may in the future have the advantage to allow for a better temporal resolution of the drug's action profile.

Adult↗
PubMed1994

Inflammation and hyperalgesia in rats neonatally treated with capsaicin: effects on two classes of nociceptive neurons in the superficial dorsal horn.

To address the mechanisms of hyperalgesia and dorsal horn plasticity following peripheral tissue inflammation, the effects of adjuvant-induced inflammation of the rat hindpaw on behavioral nociception and nociceptive neuronal activity in the superficial dorsal horn were examined in neonatally capsaicin-treated rats 6-8 weeks of age. Capsaicin treatment resulted in an 82% loss of unmyelinated fibers in L5 dorsal roots, a dramatic reduction of substance P-like immunoreactivity in the spinal cord, and a significant decrease in the percentage of dorsal horn nociceptive neurons that responded to C-fiber stimulation and noxious heating of the skin. The thermal nociceptive threshold was significantly increased in capsaicin-treated rats, but behavioral hyperalgesia to thermal stimuli still developed in response to inflammation. Following inflammation, there was a significant decrease in mechanical threshold and an increase in response duration to mechanical stimuli in both vehicle- and capsaicin-treated rats, suggesting that a state of mechanical hyperalgesia was also induced. The capsaicin treatment appears to have differential effects on nociceptive specific (NS) and wide-dynamic-range (WDR) neurons in inflamed rats. Expansion of the receptive fields of nociceptive neurons, a measure of the effect of inflammation-induced CNS plasticity, was less extensive for NS than for WDR neurons in capsaicin-treated rats. Compared to vehicle-treated rats, a smaller population of NS neurons, but a similar percentage of WDR neurons, had background activity in inflamed capsaicin-treated rats. C-fiber strength electrical stimulation of the sciatic nerve produced expansion of the receptive fields in a greater portion of NS neurons (53%, P < 0.05) in capsaicin- than in vehicle-treated rats (32%). There was no difference in stimulation-induced expansion of the receptive fields for WDR neurons between vehicle- or capsaicin-treated rats. An N-methyl-D-aspartate receptor antagonist, MK-801, attenuated the behavioral hyperalgesia and reduced the receptive field size of dorsal horn neurons in inflamed capsaicin- and vehicle-treated rats. The data suggest that while capsaicin-sensitive primary afferents may be involved in neuronal plasticity induced by peripheral tissue inflammation, changes in the capsaicin-insensitive WDR and NS populations are sufficient to produce thermal and mechanical hyperalgesia after the loss of capsaicin-sensitive primary afferents.

Animals↗
PubMed1994

Effects of extracorporeal shock-wave lithotripsy on referred hyperalgesia from renal/ureteral calculosis.

In patients suffering from colics due to calculosis of one upper urinary tract the evolution in time of referred parietal hyperalgesia after stone fragment elimination promoted by extracorporeal shock wave lithotripsy (ESWL) was studied. Before ESWL, all patients presented clinical evidence (positivity to dermographism and Head's procedure, pinch palpation, digital pressure and Giordano's manoeuver) and instrumental signs (significant lowering of pain threshold to electrical tissue stimulation) of cutaneous, subcutaneous and muscular tissue hyperalgesia in the lumbar region of the affected side. After ESWL, hyperalgesia decreased in the three tissues, as shown by progressive change in the clinical tests and an increase in pain threshold to electrical stimulation in relation to the extent of stone fragment expulsion. In the stone-free condition, hyperalgesia had disappeared in the skin but remained to a mild and moderate extent in the subcutaneous tissue and muscle respectively. It is concluded that the persistence in time of referred hyperalgesia is only in part linked to the continuing presence and activity of the stone in the urinary tract. To a certain extent, the phenomenon seems to become independent of the primary focus, possibly as a result of plastic neuronal changes in the central nervous system which, triggered by afferent visceral inputs, are maintained even after their removal.

Adult↗
PubMed1994

A psychophysical study of secondary hyperalgesia: evidence for increased pain to input from nociceptors.

Substantial evidence suggests that the hyperalgesia to mechanical stimuli that occurs in an area of uninjured skin surrounding a site of injury (area of secondary hyperalgesia) arises from activity in low-threshold mechanoreceptors (LTMs). In this study, we have investigated if activity in mechanically sensitive nociceptors also contributes to this secondary hyperalgesia. It is known that all woollen fabrics excite LTMs, but that only the prickly ones activate mechanically sensitive nociceptors. Therefore, we have conducted a psychophysical study using a range of prickly and non-prickly woollen fabrics applied to normal and hyperalgesic skin to assess the roles of LTMs and nociceptors in secondary hyperalgesia. We have studied in 10 normal volunteers the sensations of fabric-evoked prickle and pain in normal and hyperalgesic skin. Secondary hyperalgesia was produced by intradermal injection of capsaicin (25 micrograms) into the volar skin of the forearm. Five woollen fabrics (2 non-prickly, 2 prickly and 1 intermediate) were presented, in a blind manner, to the skin before and after the capsaicin injection. The sensation of fabric-evoked prickle was not changed in hyperalgesic skin. On the other hand, little if any pain was evoked by the fabrics when applied to normal skin, but substantial pain was produced by all fabrics when applied to hyperalgesic skin. The pain ratings were graded with the ratings of prickle so that fabrics that evoked the greatest prickle also evoked significantly more pain. The magnitude of pain increased linearly with prickle sensation; the slope of this regression function increased substantially in hyperalgesic skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system.

Cyclooxygenase (prostaglandin E2 and prostaglandin I2) and lipoxygenase [8(R), 15(S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid] products of arachidonic acid metabolism are thought to produce peripheral hyperalgesia by a direct action on the primary afferent nociceptor. In this study we investigated the possibility that these eicosanoids generate hyperalgesia through a common second messenger in the rat. We report that 8-bromo cAMP, a membrane permeable analogue of cAMP, produces a dose-dependent hyperalgesia that is not affected by treatments that interrupt indirect routes of hyperalgesia production including sympathectomy with 6-hydroxydopamine, depletion of polymorphonuclear leukocytes (a source of hyperalgesic eicosanoids) with hydroxyurea, or blockade of the cyclooxygenase pathway of arachidonic acid metabolism with indomethacin. The phosphodiesterase inhibitor isobutyl-methylxanthine markedly prolongs the hyperalgesic effect of 8-bromo cAMP as well as those of the directly acting hyperalgesic agents prostaglandin E2, prostaglandin I2 and 8(R),15(S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid. We conclude that the effect of all known hyperalgesic eicosanoids is mediated by the cAMP second messenger system and suggest, therefore, that cAMP mediates peripheral hyperalgesia in primary afferent nociceptors.

8-Bromo Cyclic Adenosine Monophosphate↗