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PubMed1994

The induction of des-Arg9-bradykinin-mediated hyperalgesia in the rat by inflammatory stimuli.

1. The B1 receptor agonist des-Arg9-BK does not induce mechanical hyperalgesia when injected into the rat knee joint at 1-100 nmol, or thermal hyperalgesia when injected intravenously up to 1 mumol/kg. 2. Bradykinin (BK), administered into the joint, (1 nmol-1 mumol) induces a mechanical hyperalgesia, which is maximal by 4 h. Co-administration of BK with Hoe 140 (5 pmol) blocked development of the hyperalgesia, whereas des-Arg9-Leu8-BK (0.5 nmol) had no effect. Intravenous BK had no effect on thermal paw withdrawal latencies up to 1 mumol/kg. 3. Following joint inflammation induced by local Freund's complete adjuvant, intraarticular injection of des-Arg9-BK (0.05-10 nmol) and BK (0.5-100 nmol) caused a reduction in tolerated load. Co-administration of des-Arg9-Leu8-BK (0.5 nmol) with des-Arg9-BK (0.5 nmol) blocked development of the hyperalgesia, whereas Hoe 140 (5 pmol) had no effect. BK (1 nmol)-induced hyperalgesia was blocked by Hoe 140 but not des-Arg9-Leu8-BK. 4. Following UV irradiation of the paw, intravenous des-Arg9-BK and BK reduced paw withdrawal latencies to a noxious thermal stimulus indicating thermal hyperalgesia. The latency reduction induced by des-Arg9-BK and BK was prevented with co-administration of des-Arg9-Leu8-BK 200 nmol/kg, but not with Hoe 140 0.5 mumol/kg. 5. After interleukin-1 beta pre-treatment (1 unit into the joint or paw) des-Arg9-BK induced both thermal and mechanical hyperalgesia. Co-administration of des-Arg9-Leu8-BK 0.5 nmol with des-Arg9-BK 0.5 nmol into the joint prevented development of hyperalgesia and co-administration of des-Arg9-Leu8-BK (200 nmol/kg, iv) with des-Arg9-BK 10 nmol/kg prevented reduction of thermal withdrawal latencies. 6. These data suggest that after an inflammatory insult B1 receptors may play a role in the transduction of nociceptive information.

Animals↗
PubMed1998

Effect of COX-1 and COX-2 inhibition on induction and maintenance of carrageenan-evoked thermal hyperalgesia in rats.

Intrathecal administration of nonsteroidal anti-inflammatory drugs in the rat blocks the thermal hyperalgesia induced by tissue injury, which suggests a role for spinal cyclooxygenase (COX) products in this facilitated state. Two isozymes of the COX enzyme have been reported, COX-1 and COX-2, but the agents thus far examined are not isozyme selective. We examined the effects of intrathecally (i.t.) or systemically (i.p.) administered S(+)-ibuprofen (a nonselective COX inhibitor) or 1-[(4-methysulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl) pyrazole (SC58125; a COX-2 selective inhibitor) on carrageenan-induced thermal hyperalgesia (reduced hindpaw-withdrawal latency). The following observations were made: 1) Thermal hyperalgesia otherwise observed during the first 170 min was blocked in a dose-dependent manner by S(+)-ibuprofen or SC58125 administered i.t. or i.p. before carrageenan treatment. 2) Intraperitoneal, but not i.t., administration of either inhibitor after the establishment of hyperalgesia (170 min after carrageenan injection) reversed thermal hyperalgesia in a dose-dependent manner. Thus, the initial component of thermal hyperalgesia after tissue injury was blocked by systemic or spinal administration of both COX inhibitors, whereas established hyperalgesia was reversed only by systemic inhibitors. This study demonstrates that at least spinal COX-2, if not both COX-1 and COX-2, are necessary for the initiation of thermal hyperalgesia, whereas nonspinal sources of prostanoids (synthesized by COX-2 and perhaps also COX-1) are important for the maintenance of thermal hyperalgesia associated with tissue injury and inflammation.

Animals↗
PubMed1999

Time course of UVA- and UVB-induced inflammation and hyperalgesia in human skin.

Dose-dependency and time course of hyperalgesia and erythema following UVA (16.8 and 36 J/cm(2)) and UVB (one and three times the minimum erythema threshold) irradiation was investigated in 10 healthy human subjects. Skin patches (1.5 cm in diameter) on the ventral side of the upper leg were irradiated with UVA or UVB light. Hyperaemia (Laser Doppler flowmetry, infrared thermography), thermal hyperalgesia to radiant heat stimuli, and mechanical hyperalgesia to controlled impact stimuli were tested at 1, 6, 12, 24, 48 and 96 h after irradiation. Dose-dependent delayed hyperaemia and hyperalgesia was induced only by UVB irradiation. UVB-induced increase in blood flow peaked at 12 h after irradiation and normalized by 96 h. Although superficial blood flow, as measured by Laser Doppler flowmetry, increased up to eight-fold, no significant increase of skin temperature was detected using infrared thermography. Development of mechanical and thermal hyperalgesia was delayed and reached a plateau between 24 and 48 h. In contrast to UVB, UVA irradiation of up to 36 J/cm(2), sufficient to produce intense tanning of the skin, did not induce significant hyperalgesia or delayed hyperaemia. It is concluded that UVB- but not UVA-irradiation is a suitable experimental model of subacute thermal and mechanical hyperalgesia. The different time courses of erythema and hyperalgesia indicate that inflammatory mediators responsible for vasodilatation are not identical with those inducing hyperalgesia. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗
PubMed1993

Mechanical hyperalgesias in neuropathic pain patients: dynamic and static subtypes.

Two behavioral kinds of mechanical hyperalgesia can be clearly discerned by clinical criteria in patients with neuropathic syndromes, i.e., a dynamic type, elicitable by lightly stroking the symptomatic skin, and a static type, elicitable by steadily applying gentle pressure on it. Of 28 patients studied, 19 had dynamic and 18 had static type mechanical hyperalgesia (9 expressed both types). Experimental compression-ischemia nerve block totally abolished the dynamic hyperalgesia in all patients except in 2, in whom it was markedly diminished. Disappearance of dynamic hyperalgesia occurred contemporaneously with block of myelinated A fibers, as expressed by abolition of the sensations of touch and cold, monitored quantitatively. Static hyperalgesia, however, outlasted A-fiber block in 15 of 18 patients; the phenomenon persisted during the stage when only unmyelinated fibers were available for impulse conduction. It is thus concluded that, at the primary afferent level, dynamic hyperalgesia is mediated by myelinated fibers, whereas static hyperalgesia depends on unmyelinated afferents. These two kinds of hyperalgesia represent discrete pathophysiological entities with distinct clinical connotations.

Adult↗
PubMed2003

Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice.

Endothelin receptors have been involved in inflammatory, neuropathic and tumoral pain. In the case of inflammatory hyperalgesia, some previous papers have pointed towards the involvement of ETB receptors, although the stimulation of ETA receptors seems to participate in the development of the inflammatory reaction. We have studied the effect of ETA and ETB receptor antagonists in the thermal and mechanical hyperalgesia induced in a model of acute (induced by carrageenan) and chronic (induced by complete Freund's adjuvant, CFA) inflammation in mice. The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this. In contrast, both BQ-123 (3-17.7 nmol) and BQ-788 (3-17.7 nmol) antagonized the mechanical hyperalgesia, as assessed by the Randall-Selitto test in carrageenan- and CFA-treated mice. Both BQ-123 and BQ-788 were able to antagonize the mechanical hyperalgesia induced by ET-1 (200 pmol; i.pl.) in the same dose range. Thus, ETA receptors are involved in both thermal and mechanical hyperalgesia whereas ETB receptors are only involved in mechanical hyperalgesia in these inflammatory models. In conclusion, the role of ETB receptors in inflammatory pain is further supported and new insights into the participation of ETA receptors in inflammatory hyperalgesia are given.

Animals↗
PubMed2002

Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E(2) and epinephrine in the rat.

We evaluated the role of lipoxygenase products of arachidonic acid metabolism in mechanical hyperalgesia induced by epinephrine, an agent that directly sensitizes nociceptors to produce mechanical hyperalgesia via three second messenger signaling pathways, protein kinase A (PKA), protein kinase C epsilon (PKCepsilon), and mitogen activated protein kinase (MAPK). Epinephrine hyperalgesia and that induced by a selective activator of PKCepsilon, psiepsilonRACK, were inhibited by nordihydroguaretic acid (NDGA, non-selective lipoxygenase inhibitor), baicalein (BAIC, 12-lipoxygenase inhibitor) and 5, 6-dehydroarachidonic acid (5, 6-dhAA, 5-lipoxygenase inhibitor). NDGA and 5, 6-dhAA inhibited the hyperalgesia associated with activation of the protein kinase A pathway, elicited by the direct-acting hyperalgesic agent prostaglandin E(2) or by the catalytic subunit of protein kinase A. The hyperalgesia produced by active MAPK was not blocked by any of the lipoxygenase inhibitors. Injection of 5- and 12-lipoxygenase produced hyperalgesia that was not antagonized by inhibitors of PKA, PKCepsilon or MAPK. These findings suggest that: (1). lipoxygenase products of arachidonic acid function as second messengers in the peripheral hyperalgesia induced by agents that act directly on primary afferent nociceptors (epinephrine and prostaglandin E(2)), (2). products of the 5-lipoxygenase and 12-lipoxygenase pathway are involved in this function, and (3). these lipoxygenase products contribute to hyperalgesia at or downstream of protein kinase A and PKCepsilon.

Adrenergic Agonists↗
PubMed1992

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy.

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Peripheral hyperalgesia in experimental neuropathy: exacerbation by neuropeptide Y.

Injury of peripheral nerves often results in hyperalgesia (an increased sensitivity to painful stimuli). This hyperalgesia is mediated in part by sympathetic neurotransmitters. We examined the effect of neuropeptide Y (NPY), specific Y1 and Y2 agonists, and an NPY antagonist on peripheral hyperalgesia in rats whose sciatic nerves had been partially transected. NPY and the Y2 agonist, N-acetyl [Leu28,Leu31] NPY 24-36 exacerbated both mechanical and thermal hyperalgesia, while the Y1 agonist, [Leu31, Pro34]NPY relieved thermal hyperalgesia. Mechanical and thermal hyperalgesia were both relieved by alpha-trinositol (PP56), a non-competitive antagonist of the actions of neuropeptide Y. Hyperalgesia was also relieved by surgical sympathectomy, which eliminated the effects of NPY and its agonists. These results suggest that neuropeptide Y contributes to peripheral hyperalgesia by actions at Y2 receptors, which may be located on postganglionic sympathetic terminals.

Animals↗
PubMed1995

Effect of NMDA receptor antagonists on prostaglandin E2-induced hyperalgesia in conscious mice.

Intrathecal (i.t.) injection of prostaglandin E2 (PGE2) to conscious mice produced a hyperalgesic action over a wide range of dosages with two apparent peaks at 100 pg and 10 ng per mouse, which may be mediated through EP3 and EP2 subtypes of the PGE receptor. In the present study, the effects of NMDA receptor antagonists on hyperalgesia induced by PGE2 were evaluated by the hot plate test at 30 min after i.t. injection. Hyperalgesia induced by a higher dose of PGE2 (10 ng/mouse) was relieved by D-AP5 (a competitive antagonist), 7-Cl-KynA (a glycine site antagonist), and ketamine and MK801 (non-competitive channel blockers). Intrathecal injection of butaprost (10 ng/mouse), an EP2 agonist, induced hyperalgesia, and this hyperalgesia was blocked by D-AP5, 7-Cl-KynA, ketamine, and MK801, similar to that induced by 10 ng of PGE2. On the other hand, hyperalgesia induced by a lower dose of PGE2 (100 pg/mouse) was blocked by D-AP5 and 7-Cl-KynA, but not by ketamine and MK801. Intrathecal injection of sulprostone (100 pg/mouse), an EP1 and EP3 agonist, induced hyperalgesia, and this hyperalgesia was blocked by D-AP5 and 7-Cl-KynA, but not by ketamine and MK801, similar to that induced by 100 pg of PGE2. These results first demonstrate that the NMDA receptor is involved in the PGE2-induced hyperalgesia and suggest that the hyperalgesic action by lower and higher doses of PGE2 may be mediated through EP3 and EP2 subtypes, respectively.

Alprostadil↗
PubMed1989

Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin.

Psychophysical measurements of pain and mechanical hyperalgesia were obtained following different doses of capsaicin injected intradermally into the forearms of human subjects. Each subject received a 10 microliter injection of the vehicle and capsaicin doses of 0.01, 0.1, 1, 10 and 100 micrograms. The relationship between capsaicin dose and the magnitude and duration of pain was determined using the method of magnitude estimation. In addition to pain, capsaicin produced a flare and mechanical hyperalgesia. The area of flare and the area and time course of mechanical hyperalgesia were measured as a function of the dose of capsaicin. The magnitude and duration of pain, based on averaged responses of all subjects, increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce more pain than the vehicle was 0.1 micrograms. The area and duration of mechanical hyperalgesia also increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce an area of mechanical hyperalgesia was 0.1 micrograms. An area of hyperalgesia was present within seconds following injection. For doses of 10 and 100 micrograms, the area of hyperalgesia grew to reach a maximum within 5 and 7 min following the injection and gradually decreased, disappearing within 15 and 137 min, respectively. Capsaicin doses of 1, 10 and 100 micrograms produced successively greater areas of flare. The results demonstrate that humans can scale the magnitude of pain produced by capsaicin in a dose-dependent fashion. Further, the duration of pain, the area and duration of mechanical hyperalgesia, and the area of flare are dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsaicin↗
PubMed1994

Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists.

Hyperalgesia and allodynia in 4 cancer patients treated with morphine disappeared after discontinuing or substituting morphine with other opioid agonists. The first case describes a young female who developed hyperalgesia and myoclonus during intravenous morphine infusion. The hyperalgesia and myoclonus disappeared when the morphine administration was discontinued and she felt comfortable on small and sporadic oral doses of methadone. The second case describes hyperalgesia occurring after a small dose of sustained-release morphine which disappeared after alternative use of oral ketobemidone. The third case describes hyperalgesia following high doses of intramuscular morphine which disappeared after alternative use of continuous subcutaneous infusion of sufentanil. The fourth case describes a boy developing hyperalgesia after high doses of oral and intramuscular morphine. The hyperalgesia disappeared after discontinuing morphine administration but withdrawal symptoms developed due to too small doses of methadone. Possible mechanisms of morphine-induced hyperalgesia are discussed.

Adult↗
PubMed1996

The spinal contribution of substance P to the generation and maintenance of inflammatory hyperalgesia in the rat.

That substance P (SP) contributes in some way to spinal nociceptive processing has been known for many years. However, the contribution of SP and NK-1 receptors to the generation and maintenance of inflammatory hyperalgesia or persistent chemical hyperalgesia is not clear. The purpose of this study was to test the hypothesis that SP contributes to the generation but not maintenance of hyperalgesia using two models of inflammatory pain: carrageenan, which allows for testing of acute noxious thermal and mechanical stimuli, and formalin, a model of spontaneous pain. Intrathecal pretreatment with the NK-1 receptor antagonist CP-96,345 (100, 50, 25 nmol) dose-dependently attenuated the thermal (46%, 27% and 16%, respectively) and mechanical (66%, 37% and 3%, respectively) hyperalgesia produced by 2 mg carrageenan, but not 6 mg carrageenan, 3 h after the induction of inflammation. The attenuation was still apparent at 5 h for the greatest dose, but at 7 h the magnitude of hyperalgesia was equal to rats pretreated with saline. Posttreatment with 100 nmol CP-96,345 following the establishment of hyperalgesia had no effect. Intrathecal pretreatment with 125 nmol CP-96,345 prior to formalin (1% or 5%) injection into the hindpaw produced an overall 29% or 23% attenuation, respectively, of the nociceptive behavior during the 1-h observation period. For both 1% and 5% formalin injections, the phase 2 response, but not the phase 1 response, was significantly lower than that from rats pretreated both saline. Pretreatment with 100 or 125 nmol of the inactive enantiomer, CP-96,344, was no different than pretreatment with saline. A dose of 250 nmol CP-96,345 produced voluntary paralysis yet the flexion reflex to noxious pinch remained. These results support the hypothesis that SP contributes to the generation of inflammatory hyperalgesia but once established, the contribution of SP to maintaining the state of hyperalgesia is reduced. The interaction of SP, NK-1 receptors and spinal NMDA receptors in relation to inflammatory pain is discussed.

Animals↗
PubMed1990

Characterization of distinct phospholipases mediating bradykinin and noradrenaline hyperalgesia.

Specific prostaglandins have been identified that mediate the sympathetic postganglionic neuron-terminal dependent hyperalgesia induced by bradykinin and norepinephrine, prostaglandin E2 and prostacyclin, respectively. In this study we evaluated the hypothesis that bradykinin and norepinephrine stimulate prostaglandin production in the rat, via distinct phospholipases. We found that, in normal skin, bradykinin hyperalgesia is inhibited by the phospholipase A2 inhibitor, mepacrine, but not by the phospholipase C inhibitor, neomycin and is mimicked by phospholipase A2. In chloroform-treated skin or when co-injected with A23187, bradykinin-induced hyperalgesia was found to consist of two components, one resulting from prostaglandin E2 synthesis (phospholipase A2-dependent) and one resulting from prostacyclin synthesis (phospholipase C-dependent). This latter component is blocked by Quin 2 and verapamil and also inhibited by yohimbine, an alpha 2 receptor antagonist. Arachidonic acid induces a dose-dependent hyperalgesia that was found to be like bradykinin-hyperalgesia in untreated skin (prostaglandin E2-mediated and phospholipase A2-dependent). In chloroform-treated skin or in the presence of A23187, arachidonic acid like bradykinin led to the production of prostacyclin as well as prostaglandin E2. Norepinephrine does not produce hyperalgesia in untreated skin, but in chloroform pretreated skin or in the presence of the calcium ionophore A23187, norepinephrine produces a potent dose-dependent hyperalgesia. This hyperalgesia is prevented by sympathectomy and suppressed by the calcium antagonists Quin 2 and verapamil. It is also suppressed by indomethacin and neomycin but not by SC19220 and mepacrine and is mimicked by phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed2004

A parametric study of electroacupuncture on persistent hyperalgesia and Fos protein expression in rats.

We previously reported the anti-hyperalgesia of electroacupuncture (EA) on persistent inflammatory pain in an unrestrained, unsedated, and conscious rat model. Using this model, induced by injecting complete Freund's adjuvant (CFA) into one hind paw, we systematically evaluated the anti-hyperalgesia of EA stimulation parameters (frequency, intensity, treatment duration, and pulse width). We assessed hyperalgesia by paw withdrawal latency (PWL) to a noxious thermal stimulus and found that 10- and 100-Hz EA frequencies at a current intensity of 3 mA produced the greatest anti-hyperalgesia, when compared to other parameters. Both frequencies significantly increased PWL in the early phases of hyperalgesia (2.5 and 24 h; p < 0.05), and 10 Hz EA also significantly increased PWL in later phases (5 to 7 days; p < 0.05). A sufficient but tolerable intensity of 3 mA was more effective than lower intensities (1-2 mA). A 20-min treatment produced better anti-hyperalgesia than longer and shorter (10 and 30 min) treatments. Acupoint specificity study demonstrated that GB30 produced significant EA anti-hyperalgesia, while Waiguan (TE5) and sham points, an abdominal point and a point at the opposite aspect of GB30, did not. The spinal Fos protein expression study demonstrated that the optimal EA selectively suppressed Fos expression in superficial laminae (I/II) and activated it in deeper laminae (III/IV) of the spinal dorsal horn. The results suggest that the EA anti-hyperalgesia is parameter-dependent and point-specific, and they provide important information for designing further clinical acupuncture research on persistent inflammatory pain.

Analysis of Variance↗
PubMed2006

TrkA and PKC-epsilon in thermal burn-induced mechanical hyperalgesia in the rat.

UNLABELLED: Although mechanical hyperalgesia associated with medical procedures is the major source of severe pain in burn-injured patients, little is known about its underlying mechanism. One reason for this has been the lack of a model for mechanical hyperalgesia at the site of injury. We have modified an established partial-thickness burn model in the rat to produce long-lasting primary mechanical hyperalgesia, which is present from the first measurement at 0.5 h, reaches a maximum at 3 days, and is still significant after 7 days. Because nerve growth factor (NGF), which is elevated in burn-injured tissue, produces mechanical hyperalgesia and activates protein kinase C (PKC)-epsilon, a key mediator in inflammatory and neuropathic pain, we used this model to evaluate the role of the NGF receptor, tyrosine-receptor kinase A (TrkA), and PKC-epsilon in burn-induced primary mechanical hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides to TrkA and PKC-epsilon, starting 3 days before inducing a burn injury, caused dose-related decrease of burn-induced primary mechanical hyperalgesia. In addition, intradermal injection of a PKC-epsilon-selective inhibitor eliminated hyperalgesia. Our model provides a method to elucidate the underlying mechanism of burn-injury pain as well as to screen for targets for novel analgesic treatments of this important clinical condition. PERSPECTIVE: This manuscript presents the first model of thermal injury-induced mechanical hyperalgesia which mimics prolonged duration of clinical burn injury pain. We also perform proof of concept experiments demonstrating that our model provides a method to elucidate the mechanism of this important clinical condition.

Animals↗
PubMed2005

Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury.

Neuropathic pain after nerve injury is severe and intractable, and current drugs and nondrug therapies offer substantial pain relief to no more than half of affected patients. The present study investigated the analgesic roles of the B vitamins thiamine (B1), pyridoxine (B6) and cyanocobalamin (B12) in rats with neuropathic pain caused by spinal ganglia compression (CCD) or loose ligation of the sciatic nerve (CCI). Thermal hyperalgesia was determined by a significantly shortened latency of foot withdrawal to radiant heat, and mechanical hyperalgesia was determined by a significantly decreased threshold of foot withdrawal to von Frey filaments stimulation of the plantar surface of hindpaw. Results showed that (1) intraperitoneal injection of B1 (5, 10, 33 and 100 mg/kg), B6 (33 and 100 mg/kg) or B12 (0.5 and 2 mg/kg) significantly reduced thermal hyperalgesia; (2) the combination of B1, B6 and B12 synergistically inhibited thermal hyperalgesia; (3) repetitive administration of vitamin B complex (containing B1/B6/B12 33/33/0.5 mg/kg, for 1 and 2 wk) produced long-term inhibition of thermal hyperalgesia; and (4) B vitamins did not affect mechanical hyperalgesia or normal pain sensation, and exhibited similar effects on CCD and CCI induced-hyperalgesia. The present studies demonstrate effects of B vitamins on pain and hyperalgesia following primary sensory neurons injury, and suggest the possible clinical utility of B vitamins in the treatment of neuropathic painful conditions following injury, inflammation, degeneration or other disorders in the nervous systems in human beings.

Animals↗
PubMed2006

Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats.

Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5-hydroxytryptamine (5-HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5-HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). Mechanical allodynia was assessed by paw withdrawal thresholds using von Frey filaments, and thermal hyperalgesia was assessed by paw withdrawal latencies upon exposure to a radiant heat source. Intraperitoneal administration (30-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated secondary mechanical allodynia in a dose-dependent manner. Intraperitoneal administration (3-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated primary thermal hyperalgesia in a dose-dependent manner. Intraplantar injection of sarpogrelate (300 microg) to the contralateral hindpaw had no effect on primary thermal hyperalgesia or secondary mechanical allodynia in the ipsilateral paw. The tissue concentration of 5-HT was measured using microdialysis. Concentrations of 5-HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5-HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2A receptors.

Animals↗
PubMed1997

Comparison of the effects of nucleus tractus solitarius and ventral medial medulla lesions on illness-induced and subcutaneous formalin-induced hyperalgesias.

We have previously demonstrated that illness-inducing agents (lipopolysaccharide (LPS)) and inflammatory agents (subcutaneous (s.c.) formalin) induce hyperalgesia by similar pathways. The present series of experiments compared the effects of medullary lesions on these phenomena. These experiments demonstrate that s.c. formalin-induced hyperalgesia, like illness-induced hyperalgesia, is dependent on the nucleus raphe magnus (NRM) but independent of the nucleus reticularis paragigantocellularis (NRPgc). However, these two forms of hyperalgesia differ with regards to their dependence on the nucleus tractus solitarius (NTS). Illness-induced hyperalgesia is abolished by unilateral (left) NTS lesions, whereas formalin-induced hyperalgesia remains unaffected by this procedure. These data provide further evidence that hyperalgesias induced by illness agents and by inflammatory agents are mediated by similar but not identical pathways. They also illustrate that neural structures have the capacity for opposed actions, in that both the NTS and NRM are documented to underlie hyperalgesia as well as analgesia. This capacity for opposed action may prove to be characteristic of structures involved in pain modulation.

Animals↗