APITOXINA & DOLOR
| 1: Brain Res. 2006 Jan 31; [Epub ahead of print] |
Antinociceptive
effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory
pain in the rat model of collagen-induced arthritis: Mediation by alpha(2)-Adrenoceptors.
Baek
YH, Huh
JE, Lee
JD, Choi
DY, Park
DS.
Department of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung
Hee University, #1 Hoegidong, Dongdaemungu, Seoul 130-702, South Korea.
The antinociceptive effect and the mechanism of bee venom acupuncture (BVA)
on inflammatory pain, especially in the rat model of collagen-induced arthritis
(CIA), have not yet been fully studied. This study was designed to investigate
the antinociceptive effect and its mu-opioid and alpha(2)-adrenergic mechanism
of BVA in the CIA rat model. To induce CIA, male Sprague-Dawley rats were
immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant
followed by a booster injection 14 days later. The antinociceptive effect
was evaluated by tail flick latency (TFL). After induction of arthritis, the
inflammatory pain threshold decreased as time passed, and there was no big
change of the pain threshold after 3 weeks. Three weeks after the first immunization,
BVA (0.25 mg/kg) injected into the Zusanli acupoint (ST(36)) showed the antinociceptive
effect. Furthermore, the antinociceptive effect of BVA was blocked by yohimbine
(alpha(2)-adrenergic receptor antagonist, 2 mg/kg, i.p) pretreatment, but
not by naloxone (mu-opioid receptor antagonist, 2 mg/kg, i.p.) pretreatment.
These results suggest that BVA can relieve inflammatory pain in CIA and the
antinociceptive effect of BVA can be mediated by alpha(2)-adrenergic receptor.
PMID: 16457792 [PubMed - as supplied by publisher]
| 2: Neuroscience. 2006;138(2):631-640. Epub 2006 Jan 30. |
Effects of
bee venom peptidergic components on rat pain-related behaviors and inflammation.
Chen YN, Li KC, Li Z, Shang GW, Liu DN, Lu ZM, Zhang JW, Ji YH, Gao GD, Chen J.
Institute for Functional Brain
Disorders and Institute for Biomedical Sciences of Pain, Tangdu Hospital,
Fourth Military Medical University, #1 Xinsi Road, Baqiao, Xi'an 710038, PR
China.
To identify the active components of honeybee venom in production of inflammation
and pain-related behaviors, five major peptidergic subfractions were separated,
purified and identified from the whole honeybee venom. Among them, four active
peptidergic components were characterized as apamin, mast-cell degranulating
peptide (MCDP), phospholipase A(2) (PLA(2))-related peptide and melittin,
respectively. All five subfractions were effective in production of local
inflammatory responses (paw edema) in rats although the efficacies were different.
Among the five identified subfractions, only MCDP, PLA(2)-related peptide
and melittin were able to produce ongoing pain-related behaviors shown as
paw flinches, while only apamin and melittin were potent to produce both thermal
and mechanical hypersensitivity. As shown in our previous report, melittin
was the most potent polypeptide in production of local inflammation as well
as ongoing pain and hypersensitivity. To further explore the peripheral mechanisms
underlying melittin-induced nociception and hypersensitivity, a single dose
of capsazepine, a blocker of thermal nociceptor transient receptor potential
vanilloid receptor 1, was treated s.c. prior to or after melittin administration.
The results showed that both pre- and post-treatment of capsazepine could
significantly prevent and suppress the melittin-induced ongoing nociceptive
responses and thermal hypersensitivity, but were without influencing mechanical
hypersensitivity. The present results suggest that the naturally occurring
peptidergic substances of the whole honeybee venom have various pharmacological
potencies to produce local inflammation, nociception and pain hypersensitivity
in mammals, and among the five identified reverse-phase high pressure liquid
chromatography subfractions (four polypeptides), melittin, a polypeptide occupying
over 50% of the whole honeybee venom, plays a central role in production of
local inflammation, nociception and hyperalgesia or allodynia following the
experimental honeybee's sting. Peripheral transient receptor potential vanilloid
receptor 1 is likely to be involved in melittin-produced ongoing pain and
heat hyperalgesia, but not mechanical hyperalgesia, in rats.
PMID: 16446039 [PubMed - as supplied by publisher]
| 3: Nurs Stand. 2005 Nov 2-8;20(8):22-4. |
It's all the buzz.
O'Connell
N.
Although honey has been used medicinally for thousands of years, bee products
have only recently become the subject of in depth medical research. Wound
healing products containing honey are now available. Bee venom has been used
to treat painful conditions. Propolis is a potent anti-inflammatory agent.
Broad claims have been made for royal jelly.
PMID: 16295595 [PubMed - indexed for MEDLINE]
| 4: Exp Neurol. 2005 Sep;195(1):148-60. |
Unilateral
subcutaneous bee venom but not formalin injection causes contralateral hypersensitized
wind-up and after-discharge of the spinal withdrawal reflex in anesthetized
spinal rats.
You
HJ, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction (SMI), Laboratory for Experimental Pain
Research, Aalborg University, Fredrik Bajers Vej 7 D-3, DK-9220 Aalborg, Denmark.
This study aimed to investigate the effect of tonic nociception on spinal
withdrawal reflexes including (1) long lasting spontaneous responses elicited
by subcutaneous (s.c.) administration of formalin (2.5%, 50 microl) and bee
venom (BV, 0.2 mg/50 microl) into the hind paw and (2) corresponding ipsilateral
(primary) and contralateral (secondary) hypersensitivity to noxious pinch
and repetitive supra-threshold (1.5 x T) electrical stimuli at different frequencies
(3 Hz: wind-up; 20 Hz: after-discharge) in anesthetized spinal rats. Spinal
withdrawal reflexes were studied by simultaneously assessing single motor
units (SMUs) electromyographic (EMG) activities from the bilateral medial
gastrocnemius (MG) muscles. Subcutaneous formalin-induced persistent spontaneous
SMU EMG responses were in typical biphasic manner with an apparent silent
period (about 13-18 min), but in contrast, BV elicited monophasic long lasting
(about 1 h) SMU EMG responses without any resting state. The mechanically
and electrically evoked responsiveness of SMUs were enhanced significantly
by ipsilateral BV injection, whereas enhanced electrically, but not mechanically,
evoked responses (including wind-up and after-discharge) were found at the
non-injection site of the contralateral hind paw. However,
| 5: J Pharmacol Exp Ther. 2005 Sep;314(3):1353-61. Epub 2005 Jun 9. |
Tertiapin-Q
blocks recombinant and native large conductance K+ channels in a use-dependent
manner.
Kanjhan
R, Coulson
EJ, Adams
DJ, Bellingham
MC.
School of Biomedical Sciences,
Tertiapin, a short peptide from honey bee venom, has been reported to specifically
block the inwardly rectifying K(+) (Kir) channels, including G protein-coupled
inwardly rectifying potassium channel (GIRK) 1+GIRK4 heteromultimers and ROMK1
homomultimers. In the present study, the effects of a stable and functionally
similar derivative of tertiapin, tertiapin-Q, were examined on recombinant
human voltage-dependent Ca(2+)-activated large conductance K(+) channel (BK
or MaxiK; alpha-subunit or hSlo1 homomultimers) and mouse inwardly rectifying
GIRK1+GIRK2 (i.e., Kir3.1 and Kir3.2) heteromultimeric K(+) channels expressed
in Xenopus oocytes and in cultured newborn mouse dorsal root ganglion (DRG)
neurons. In two-electrode voltage-clamped oocytes, tertiapin-Q (1-100 nM)
inhibited BK-type K(+) channels in a use- and concentration-dependent manner.
We also confirmed the inhibition of recombinant GIRK1+GIRK2 heteromultimers
by tertiapin-Q, which had no effect on endogenous depolarization- and hyperpolarization-activated
currents sensitive to extracellular divalent cations (Ca(2+), Mg(2+), Zn(2+),
and Ba(2+)) in defolliculated oocytes. In voltage-clamped DRG neurons, tertiapin-Q
voltage- and use-dependently inhibited outwardly rectifying K(+) currents,
but Cs(+)-blocked hyperpolarization-activated inward currents including I(H)
were insensitive to tertiapin-Q, baclofen, barium, and zinc, suggesting absence
of functional GIRK channels in the newborn. Under current-clamp conditions,
tertiapin-Q blocked the action potential after hyperpolarization (AHP) and
increased action potential duration in DRG neurons. Taken together, these
results demonstrate that the blocking actions of tertiapin-Q are not specific
to Kir channels and that the blockade of recombinant BK channels and native
neuronal AHP currents is use-dependent. Inhibition of specific types of Kir
and voltage-dependent Ca(2+)-activated K(+) channels by tertiapin-Q at nanomolar
range via different mechanisms may have implications in pain physiology and
therapy.
| 6: Toxicon. 2005 Jul;46(1):39-45. |
Bee venom
induces apoptosis through caspase-3 activation in synovial fibroblasts of
patients with rheumatoid arthritis.
Hong SJ, Rim GS, Yang HI, Yin CS, Koh HG, Jang MH, Kim CJ, Choe BK, Chung JH.
Department of Internal Medicine,
College of Medicine, Pochon CHA University, 351 Yatap-dong, Bundang-gu, Sungnam-si,
Kyonggi-do 463-712, South Korea.
Bee venom (BV) has been used traditionally for the control of pain and inflammation
in various chronic inflammatory diseases, including rheumatoid arthritis (RA)
in Oriental medicine. However, it is still unclear how BV exerts its beneficial
effects on the clinical course of RA patients. To investigate the effect of
BV on the treatment of rheumatoid synovitis, we examined the inhibition of
cell growth and induction of apoptosis in human rheumatoid synovial fibroblasts.
Rheumatoid synovial fibroblasts were surgically obtained from patients with
RA. Cell proliferation and viability were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay. The apoptosis of synovial cells treated with 10 microg/ml
BV for 24 h was identified by 4,6-diamidino-2-phenylindole (DAPI) staining,
terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL)
assay, DNA fragmentation assay, RT-PCR, and Western blot analysis. It was
demonstrated that rheumatoid synovial cells treated with 10 microg/ml BV for
24 h exhibited apoptotic features and fragmentation of DNA. In addition, BV
induces apoptosis in rheumatoid synovial cells through a decrease in BCL2
expression and an increase in BAX and caspase-3 (CASP3) expression. It is
suggested that BV inhibits the proliferation of rheumatoid synovial cells
through induction of apoptosis by CASP3 activation.
PMID: 15922390 [PubMed - indexed for MEDLINE]
| 7: Neurosci Lett. 2005 Jun 10-17;381(1-2):194-8. Epub 2005 Mar 2. |
Activation
of spinal extracellular signaling-regulated kinases by intraplantar melittin
injection.
Yu YQ, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, PR China.
Intraplantar injection of melittin, a major toxic peptide of whole bee venom,
has been proved to cause alteration in both behavioral and spinal neuronal
responses in rats. To see whether extracellular signaling-regulated kinases
(ERK) in the spinal cord dorsal horn are activated and involved in induction
and maintenance of persistent ongoing nociception, pain hypersensitivity and
inflammation, three doses of U0126 (1,4-diamino-2,3-dicyano-1, 4-bis-[o-aminophenylmercapto]butadiene),
a widely used specific MAP kinase kinase (MEK) inhibitor, were administered
through chronic intrathecal catheterization prior to or after intraplantar
injection of melittin. We found that: (1) the induction of melittin-induced
persistent spontaneous nociception (PSN), mechanical and heat hypersensitivity
could be suppressed by U0126 in a dose-related manner; (2) specific inhibition
of ERK pathway suppressed the maintenance of melittin-induced PSN and heat
hypersensitivity, while established mechanical hypersensitivity could not
be reversed; and (3) intrathecal administration of U0126 had no effects on
peripheral inflammation induced by melittin. This result suggests that spinal
ERK pathway might be a common factor involved in inducing and maintaining
pathophysiological processes of ongoing pain and heat hyperalgesia, while
the role of ERK pathway in generation of the mechanical hypersensitivity is
not consistent and remains to be further clarified.
PMID: 15882816 [PubMed - indexed for MEDLINE]
| 8: Brain Res. 2005 May 10;1043(1-2):231-5. |
Evidence
for peripherally antinociceptive action of propofol in rats: behavioral and
spinal neuronal responses to subcutaneous bee venom.
Sun
YY, Li KC, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, PR China.
In the present study, behavioral and in vivo electrophysiological methods
were used to examine the peripheral effects of propofol on tonic ongoing pain-related
responses produced by subcutaneous bee venom-induced inflammatory pain state.
Local administration of 0.5 microg propofol produced significant suppression
of the well-established ongoing pain responses in both conscious rats and
dorsal horn nociceptive neurons. The locally antinociceptive action of propofol
is not caused by systemic effect, because contralateral administration of
the same dose of drug did not produce any effect. This result indicates that
besides central actions, propofol has peripherally antinociceptive action
as well.
PMID: 15862538 [PubMed - indexed for MEDLINE]
| 9: Evid Based Complement Alternat Med. 2005 Mar;2(1):79-84. |
An Overview
of Bee Venom Acupuncture in the Treatment of Arthritis.
Lee
JD, Park
HJ, Chae
Y, Lim
S.
Bee venom acupuncture (BVA), as a kind of herbal acupuncture, exerts not only
pharmacological actions from the bioactive compounds isolated from bee venom
but also a mechanical function from acupuncture stimulation. BVA is growing
in popularity, especially in Korea, and is used primarily for pain relief
in many kinds of diseases. We aimed to summarize and evaluate the available
evidence of BVA for rheumatoid arthritis and osteoarthritis. Computerized
literature searches for experimental studies and clinical trials of BVA for
arthritis were performed on the databases from PUBMED, EMBASE and the Cochrane
Library. In addition, two leading Korean journals (The Journal of Korean Society
for Acupuncture and Moxibustion and The Journal of Korean Oriental Medicine)
were searched for relevant studies. The search revealed 67 studies, 15 of
which met our criteria. The anti-inflammation and analgesic actions of BVA
were proved in various kinds of animal arthritic models. Two randomized controlled
trials and three uncontrolled clinical trials showed that BVA was effective
in the treatment of arthritis. It is highly likely that the effectiveness
of BVA for arthritis is a promising area of future research. However, there
is limited evidence demonstrating the efficacy of BVA in arthritis. Rigorous
trials with large sample size and adequate design are needed to define the
role of BVA for these indications. In addition, studies on the optimal dosage
and concentration of BVA are recommended for future trials.
PMID: 15841281 [PubMed - as supplied by publisher]
| 10: Neurosci Lett. 2005 Feb 25;375(1):42-6. Epub 2004 Nov 19. |
Changes of
5-HT receptor subtype mRNAs in rat dorsal root ganglion by bee venom-induced
inflammatory pain.
Liu XY, Wu SX, Wang YY, Wang W, Zhou L, Li YQ.
Department of Anatomy and K.K.
Leung Brain Research Centre, The Fourth Military Medical University, Xi'an
710032, PR China.
The reverse transcriptase polymerase chain reaction (RT-PCR) technique was
used to examine the changes of the expression of 5-hydroxytryptamine (5-HT)
receptors in the rat lumbar dorsal root ganglion (DRG) following subcutaneous
bee venom (BV) injection into the plantar surface of the unilateral hindpaw.
In the DRG ipsilateral to the BV injection, significant increase of mRNA levels
of 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(3) receptor subtypes were observed
at 1 and 4h after the BV injection, while increase of 5-HT(
| 11: Pharmacol Biochem Behav. 2005 Jan;80(1):181-7. Epub 2004 Nov 26. |
Water soluble
fraction (<10 kDa) from bee venom reduces visceral pain behavior through
spinal alpha 2-adrenergic activity in mice.
Kwon YB, Ham TW, Kim HW, Roh DH, Yoon SY, Han HJ, Yang IS, Kim KW, Beitz AJ, Lee JH.
Department of Pharmacology, Institute
for Medical Science, Chonbuk National University Medical School, Chonju, South
Korea.
We have previously shown that subcutaneous bee venom (BV) injection reduces
visceral pain behavior in mice, but it is not clear which constituent of BV
is responsible for its antinociceptive effect. In the present study, we now
demonstrate that a water-soluble subfraction of BV (BVA) reproduces the antinociceptive
effect of BV in acetic acid-induced visceral pain model. We further evaluated
three different BVA subfractions that were separated by molecular weight,
and found that only the BVAF3 subfraction (a molecular weight of <10 kDa)
produced a significant antinociceptive effect on abdominal stretches and suppressed
visceral pain-induced spinal cord Fos expression. Injection of melittin (MEL),
a major constituent of BVAF3, also produced a visceral antinociception. However,
melittin's antinociception was completely blocked by boiling for 10 min at
100 degrees C, while boiling either whole BV or BVAF3 did not prevent their
antinociception. The antinociceptive effect of BVAF3 was completely blocked
by intrathecal pretreatment with the alpha2-adrenoceptor antagonist, yohimbine
(YOH), while intrathecal pretreatment with the opioid antagonist, naloxone
(NAL) or the serotonin antagonist, methysergide, had no effect. These data
demonstrate that BVAF3 is responsible for the visceral antinociception of
whole BV and further suggest that this effect is mediated in part by spinal
alpha2-adrenergic activity.
PMID: 15652394 [PubMed - indexed for MEDLINE]
| 12: Pharmacol Res. 2005 Feb;51(2):183-8. |
Antinociceptive
mechanisms associated with diluted bee venom acupuncture (apipuncture) in
the rat formalin test: involvement of descending adrenergic and serotonergic
pathways.
Kim
HW, Kwon
YB, Han
HJ, Yang
IS, Beitz
AJ, Lee
JH.
Department of Veterinary Physiology, College of Veterinary Medicine and School
of Agricultural Biotechnology, Seoul National University, San 56-1, Shilim-dong,
Kwanak-gu, Seoul 151-742, South Korea.
In a previous report, subcutaneous injection of diluted bee venom (dBV) into
a specific acupuncture point (Zusanli, ST36), a procedure termed apipuncture,
was shown to produce an antinociceptive effect in the rat formalin pain model.
However, the central antinociceptive mechanisms responsible for this effect
have not been established. Traditional acupuncture-induced antinociception
is considered to be mediated by activation of the descending pain inhibitory
system (DPIS) including initiation of its opioidergic, adrenergic and serotonergic
components. The purpose of the present study was to investigate whether the
antinociceptive effect of apipuncture is also mediated by the DPIS. Behavioral
experiments verified that apipuncture significantly reduces licking behavior
in the late phase of formalin test in rats. This antinociceptive effect of
apipuncture was not modified by intrathecal pretreatment with naltrexone (a
non-selective opioid receptor antagonist), prazosin (an alpha1 adrenoceptor
antagonist) or propranolol (an beta adrenoceptor antagonist). In contrast,
intrathecally injected idazoxan (an alpha2 adrenoceptor antagonist) or intrathecal
methysergide (a serotonin receptor antagonist) significantly reversed apipuncture-induced
antinociception. These results suggest that apipuncture-induced antinociception
is produced by activation of alpha2 adrenergic and serotonergic components
of the DPIS.
PMID: 15629266 [PubMed - indexed for MEDLINE]
| 13: Am J Chin Med. 2004;32(3):361-7. |
Anti-inflammatory
effect of bee venom on type II collagen-induced arthritis.
Lee JD, Kim SY, Kim TW, Lee SH, Yang HI, Lee DI, Lee YH.
Research Group of Pain and Neuroscience
in Vision 2000 Project East-West Medical Research Institute, Kyung Hee University,
Seoul, Korea. ljdacu@khmc.or.kr
Bee venom (BV) has been used to relieve pain and reduce inflammation in traditional
Oriental medicine, especially in chronic inflammatory diseases such as rheumatoid
arthritis (RA). We previously reported that the BV injection into a traditional
acupuncture point (Zusanli) reduced arthritis-associated edema and nociceptive
responses in Freund's adjuvant-induced arthritis in rats (Kwon et al., 2001).
This study was designed to evaluate the anti-inflammatory and anti-cytokine
effect of BV on a murine type-II collagen-induced arthritis (CIA) model. Male
mice were immunized by spontaneous injection of 100 microg of an emulsion
of bovine type-II collagen and complete Freund's adjuvant (CFA), with a booster
injection after 2 weeks. In the experimental group, 0.1 ml BV was injected
at acupuncture point (Zusanli) near both knees twice a week for a total of
5 times. In the control group, normal saline was injected at the same frequencies.
These injections began 5 weeks after the first collagen injection. Starting
the 3rd week after the first collagen injection, we examined limb swelling
and severity of arthritis twice a week. At 8 weeks, mice were sacrificed and
synovial tissue was examined with the light microscope and serum cytokines
(IL-1beta and TNF-alpha) were measured by ELISA. The incidence of arthritis,
the mean arthritis index and the number of arthritic limbs were significantly
lower in the treatment compared to the control group (63% versus 75%, 3.4%
versus 8.5%, 23% versus 75%, respectively). Among the serum proinflammatory
cytokines, the production of TNF-alpha in the BV group was suppressed compared
to the control group (59 +/- 4.5 versus 99.5 +/- 6.5, p < 0.05), but IL-1beta
was not suppressed. The examination of the histopathology of the joints of
murine CIA showed decreased inflammation signs and less lymphocyte infiltration
after BV acupuncture therapy. Acupuncture therapy with BV suppressed the development
of arthritis and caused inhibition of the immune responses in type-II collagen-induced
arthritis.
PMID: 15344419 [PubMed - indexed for MEDLINE]
| 14: J Pain. 2004 Aug;5(6):297-303. |
Acupoint
stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia
in a rodent neuropathic pain model: involvement of spinal alpha 2-adrenoceptors.
Roh DH, Kwon YB, Kim HW, Ham TW, Yoon SY, Kang SY, Han HJ, Lee HJ, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine, Seoul National University, South Korea.
Chemical acupuncture with diluted bee venom (DBV), termed apipuncture, has
been traditionally used in oriental medicine to treat several inflammatory
diseases and chronic pain conditions. In the present study we investigated
the potential antihyperalgesic and antiallodynic effects of apipuncture in
a rat neuropathic pain model. DBV (0.25 mg/kg, subcutaneous) was injected
into the Zusanli acupoint 2 weeks after chronic constrictive injury (CCI)
of the sciatic nerve. Between 5 and 45 minutes after DBV injection, we observed
a significant reduction in the thermal hyperalgesia induced by CCI, but apipuncture
failed to reduce CCI-induced mechanical allodynia. We subsequently examined
whether this antihyperalgesic effect of apipuncture was related to the activation
of spinal opioid receptors and/or alpha2-adrenoceptors. Intrathecal pretreatment
with naloxone (10 microg/rat), an opioid receptor antagonist, did not reverse
the antihyperalgesic effect of apipuncture, whereas pretreatment with idazoxan
(40 microg/rat), an alpha2-adrenoceptor antagonist, completely blocked the
effect of apipuncture. These results indicate that DBV-induced apipuncture
significantly reduces the thermal hyperalgesia generated by CCI and also suggest
that this antihyperalgesic effect is dependent on the activation of alpha2-adrenoceptors,
but not opioid receptors, in the spinal cord. PERSPECTIVE: The antinociceptive
effect of apipuncture was evaluated in a rodent neuropathic pain model. The
relieving effect of apipuncture on thermal hyperalgesia was found to be mediated
by spinal alpha2-adrenoceptors, but not opioid receptors. These data suggest
that apipuncture might be an effective alternative therapy for patients with
painful peripheral neuropathy, especially for those who are poorly responsive
to opioid analgesics.
PMID: 15336634 [PubMed - indexed for MEDLINE]
| 15: Neuroreport. 2004 Aug 6;15(11):1745-9. |
Melittin
selectively activates capsaicin-sensitive primary afferent fibers.
Shin
HK, Kim
JH.
Department of Physiology, College of Medicine, Hanyang University, 17 Haengdang-Dong,
Seongdong-Gu, Seoul 133-791, Korea. shinhg@hanyang.ac.kr
Whole bee venom (WBV)-induced pain model has been reported to be very useful
for the study of pain. However, the major constituent responsible for the
production of pain by WBV is not apparent. Intraplantar injection of WBV and
melittin dramatically reduced mechanical threshold, and increased flinchings
and paw thickness. In behavioral experiments, capsaicin pretreatment almost
completely prevented WBV- and melittin-induced reduction of mechanical threshold
and flinchings. Intraplantar injection of melittin increased discharge rate
of dorsal horn neurons only with C fiber input from peripheral receptive field,
which was completely blocked by topical application of capsaicin to sciatic
nerve. These results suggest that both melittin and WBV induce nociceptive
responses by selective activation of capsaicin-sensitive afferent fibers.
PMID: 15257140 [PubMed - indexed for MEDLINE]
| 16: Neuroscience. 2004;126(3):753-62. |
Altered pain-related
behaviors and spinal neuronal responses produced by s.c. injection of melittin
in rats.
Li KC, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, P.R. People's Republic of China.
Recently, we have reported that following s.c. injection of a solution containing
the whole bee-venom (BV; Apis mellifera), into one hind paw of a rat, the
experimentally produced honeybee's sting, the animal shows altered pain-related
behaviors and inflammation relevant to pathological pain state. To see whether
melittin, the major (over 50%) toxic component of the BV, is responsible for
the above abnormal pain behavioral changes, the present study was designed
to investigate the effects of s.c. melittin on either nociceptive behaviors
in conscious rats or spinal dorsal horn neuronal responses in anesthetized
rats. In the behavioral surveys, s.c. injection of three doses of both melittin
(5, 25 and 50 microg) and BV (10, 50 and 100 microg) into the posterior surface
of one hind paw of rats produced an immediate tonic nociceptive response displaying
as persistent spontaneous paw flinching reflex. Similar to the BV test, the
melittin response was also monophasic and dose-dependent in terms of both
intensity and time course. As an accompanied consequence, both heat and mechanical
hypersensitivity (hyperalgesia and allodynia) and inflammatory responses (paw
swelling and plasma extravasation) were induced by s.c. melittin injections.
In the electrophysiological recordings, s.c. injection of the same three doses
of melittin into the cutaneous receptive field produced an immediate, dose-dependent
increase in spontaneous spike discharges of spinal dorsal horn wide-dynamic-range
(WDR) neurons which are believed to be responsible for the spinally-organized
nociceptive flexion reflex. The melittin-induced ongoing spike responses are
similar to the behavioral flinching reflex in terms of both duration and frequency.
Furthermore, the responsiveness of the WDR neurons to both heat (42 degrees
C, 45 degrees C, 47 degrees C and 49 degrees C) and mechanical (brush, pressure
and pinch) stimuli was significantly enhanced by s.c. injection of melittin
shown as a leftward shift of the stimulus-response functional curves. Taken
together, the present results suggest that melittin, the major toxin of the
whole BV, is likely to be responsible for production of the long-term spinal
neuronal changes as well as persistent spontaneous nociception, heat/mechanical
hypersensitivity and inflammatory responses that are produced by experimental
honeybee's sting.
PMID: 15183523 [PubMed - indexed for MEDLINE]
| 17: Sheng Li Xue Bao. 2004 Apr 25;56(2):178-82. |
Age-related
changes in deterministic behaviors of nociceptive firing of rat dorsal horn
neurons.
Zheng
JH, Feng
W, Jian
Z, Chen
J.
Pain Research Center, Institute of Neuroscience, K. K. Leung Brain Research
Centre, The Fourth Military Medical University, Xi'an 710032, China.
To demonstrate the age-related changes in the dynamics of the nociceptive
discharge of dorsal horn nociceptive neurons, the nonlinear prediction method
was used to quantify the degree of deterministic behavior within the interspike
interval series of tissue injury-induced firing of spinal nociceptive neurons
in anesthetized adult young (3-4 months) and aged (>22 months) rats. Subcutaneous
bee venom injection induced long-term discharge of spinal wide dynamic range
(WDR) neurons in both groups. However, the nociceptive discharge of single
WDR neurons in the aged group showed higher determinism when compared with
the adult young rats. This result suggests that the dynamics of single nociceptive
neurons may not remain constant throughout the life span, and this age-associated
change may be an underlying mechanism for various pain manifestations in the
elderly population.
PMID: 15127127 [PubMed - indexed for MEDLINE]
| 18: Brain Res. 2004 Mar 19;1001(1-2):143-9. |
Complexity
of tissue injury-induced nociceptive discharge of dorsal horn wide dynamic
range neurons in the rat, correlation with the effect of systemic morphine.
Zheng
JH, Chen
J, Arendt-Nielsen
L.
Pain Research Center (PRC), Institute of Neuroscience, The Fourth Military
Medical University, Xi'an 710032, PR China.
Persistent discharge of wide dynamic range (WDR) neurons was recorded from
lumbar dorsal horn of anesthetized rats following subcutaneous bee venom injection
into the receptive field. To quantitatively describe the complexity of this
nociceptive activity, we computed the approximate entropy (ApEn) for each
sampled interspike interval (ISI) series. A larger value of ApEn indicates
higher complexity or less regularity and vice versa. The ApEn value varied
across different WDR neurons tested, and for each neuron the ApEn remained
constant through the 1-h discharge though the average ISI of the sampled data
increased progressively with time (16 neurons). A low dose of intravenous
morphine (0.3 mg/kg) depressed the activity of WDR neurons differentially,
and the degree of this inhibition showed a significant correlation with the
value of ApEn (P<0.001, 27 neurons, Spearman's correlation test). The present
results suggest that the complexity feature of WDR neurons is various under
tissue injury state, and for each single WDR neuron the complexity feature
is relatively independent of the strength of peripheral noxious input and
cannot be fully described in terms of average firing rate. Moreover, the response
of the nociceptive discharge to analgesics may be related to the nonlinear
dynamics feature of nociceptive neurons, which can be quantitatively characterized
by the degree of complexity.
PMID: 14972663 [PubMed - indexed for MEDLINE]
| 19: Neurosignals. 2003 Nov-Dec;12(6):292-301. |
Differential
roles of spinal protein kinases C and a in development of primary heat and
mechanical hypersensitivity induced by subcutaneous bee venom chemical injury
in the rat.
Li KC, Chen
J.
Pain Research Center (PRC), Institute of Neuroscience, Fourth Military Medical
University, Xi'an, China.
It has been demonstrated that subcutaneous injection of bee venom (BV) can
produce different types of pain and hypersensitivity including persistent
spontaneous nociception (PSN), primary heat and mechanical hypersensitivity
(hyperalgesia) and mirror-image heat (MIH) hypersensitivity in an individual
animal, and the changes of spinal neurons are likely to be responsible for
the production of these pain-related behaviors. In this study, we examined
the roles of spinal protein kinase C (PKC) and protein kinase A (PKA) in the
BV-induced different types of pain and hypersensitivity in conscious rats.
We found that: (1). BV-induced primary heat hypersensitivity could be blocked
by intrathecal pre- or posttreatment with a PKC inhibitor, chelerythrine chloride
(CH), while a PKA inhibitor, N-(2-[P-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide
hydrochloride (H89), had no effect. (2). BV-induced primary mechanical hypersensitivity
could be blocked by pre- or posttreatment with H89, whereas CH had no effect.
(3). Both pre- and posttreatment with H89 produced suppressive effects on
both induction and maintenance of the BV-induced PSN and MIH hypersensitivity.
Based on the present findings, we proposed that spinal PKC might be activated
during the central processes of primary heat hypersensitivity, while spinal
PKA is likely to be involved in primary mechanical hypersensitivity induced
by subcutaneous BV chemical injury. Taken together with our previous report
however, spinal PKC and PKA are likely to be simultaneously involved in the
central processes of both PSN and MIH hypersensitivity. Copyright 2003 S.
Karger AG, Basel
PMID: 14739559 [PubMed - indexed for MEDLINE]
| 20: Pain. 2003 Nov;106(1-2):135-42. |
5-hydroxytryptamine1A
receptor is involved in the bee venom induced inflammatory pain.
Wang W, Wu SX, Wang YY, Liu XY, Li YQ.
Department of Anatomy and K.K.
Leung Brain Research Centre, The Fourth Military Medical University, 17 West
Chang'le Road, Xi'an 710032, People's Republic of China.
Injection of bee venom into one hindpaw of rat can elicit acute inflammation
together with spontaneous pain, heat hyperalgesia and mechanical hyperalgesia/allodynia
in the injected paw. 5-hydroxytryptamine (5-HT)1A receptor is the predominant
receptor subtype in the spinal dorsal horn mediating the function of 5-HT
in nociception. The goal of the present study is to assess the role of 5-HT1A
receptor in the pain associated with the bee venom induced inflammation. Here
we showed that 1 or 4 h after a subcutaneous bee venom challenge, expression
of 5-HT1A receptor mRNA in the ipsilateral lumbar spinal cord increased significantly
by 80.94 or 37.86%, respectively. Antisense oligodeoxynucleotide knockdown
of spinal 5-HT1A receptor attenuated spontaneous pain and reversed heat hyperalgesia
in rats injected with bee venom. Thus, the present data suggest a facilitating
role for 5-HT1A receptor in bee venom induced inflammatory pain.
PMID: 14581120 [PubMed - indexed for MEDLINE]
| 21: Sheng Li Xue Bao. 2003 Oct 25;55(5):516-24. |
Effects of
intravenous Injections Paederiae and Stauntonia on spontaneous pain, hyperalgesia
and inflammation induced by cutaneous chemical tissue injury in the rat.
Peng
XL, Gao
XL, Chen
J, Huang
X, Chen
HS.
Pain Research Center, Institute of Neuroscience, The Fourth Military Medical
University, Xi' an 710032.
To study whether commercial traditional Chinese medicinal preparations Injection
Paederiae (IP) or Injection Stauntonia (IS) has anti-nociceptive and/or anti-inflammatory
effects, we used two persistent pain models (bee venom and formalin test)
to evaluate the systemic effects of IP or IS on the chemical tissue injury-induced
persistent spontaneous pain-related responses (PSPR), primary thermal/mechanical
hyperalgesia and inflammation in conscious rats. Injection of bee venom (BV,
0.1 mg, 50 microl) into the plantar surface of one hind paw resulted in not
only a 1-h monophasic PSPR such as flinching reflex in the injected paw and
a subsequent period of 3-4 days primary heat and mechanical hyperalgesia,
but also a marked sign of inflammation, including redness and swelling of
the plantar surface in the injected paw. Intraplantar injection of formalin
produced two phases of PSPR as reported previously. Systemic pre-treatment
with three doses of IP (0.32, 1.6 and 9.0 ml/kg, 500%) or IS (0.32, 1.6 and
9.0 ml/kg, 250%) produced a dose-dependent suppression of the BV- or formalin-induced
flinching reflex of 1 h time course as compared with the saline control group.
Post-treatment with IP or IS 5 min after BV injection also produced a significant
suppression of the flinching reflex in both BV test and formalin test respectively,
as compared with the control group. However, neither pre- nor post-treatment
with IP or IS produced any significantly suppressive effect on the BV-induced
primary heat and mechanical hyperalgesia and inflammation. The analgesia produced
by IP or IS was not mediated by the endogenous opioid receptors since naloxone,
a non-selective opioid receptor antagonist, had no reversal effect on the
IP and IS-produced analgesia in the BV-induced PSPR. Our present results suggest
that IP or IS might prevent and relieve clinical persistent spontaneous pain,
but without any anti-nociceptive and anti-inflammatory effects on the primary
heat hyperalgesia, mechanical hyperalgesia, as well as inflammatory responses.
The BV test might be a useful model of pain to evaluate and screen anti-nociceptive
and anti-inflammatory effects of certain compounds of the Chinese medicinal
herbs on the pathological origins of pain.
PMID: 14566397 [PubMed - indexed for MEDLINE]
| 22: Neuroscience. 2003;121(2):459-72. |
Differential
antinociceptive effects induced by a selective cyclooxygenase-2 inhibitor
(SC-236) on dorsal horn neurons and spinal withdrawal reflexes in anesthetized
spinal rats.
You
HJ, Morch
CD, Chen
J, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research,
Aalborg University, Fredrik Bajers Vej 7D-3, DK-9220, Aalborg, Denmark. lan@smi.auc.dk
The aim of present study was to examine the effect of a selective cyclooxygenase-2
(COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal
wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius
soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold
(1.5xT, the intensity threshold) electrical stimuli with different frequencies
(3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced
inflammation and central sensitization. During normal conditions, the responses
of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli
(3 Hz, wind-up) were depressed by systemic administration of SC-236 as well
as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both
the WDR neurons and the simultaneously recorded SMUs after electrical stimuli
with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms
underlying the generation of the C-fiber mediated late responses and the after-discharges
may be different. The enhanced responsiveness of both WDR neurons and SMUs
to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia)
in the BV experiments was apparently depressed by SC-236, but not its vehicle.
For electrical stimulation, the enhanced late responses and after-discharges,
but not early responses, of both the WDR neurons and the simultaneously recorded
SMUs were markedly depressed only by SC-236. This indicates that different
central pharmacological mechanisms underlie the generation of these enhanced
early, late responses, and after-discharges during BV-induced inflammation.
The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities
of both spinal cord dorsal horn neuron and spinal withdrawal reflex during
BV-induced sensitization, indicating that COX-2 plays an important role in
the maintenance of central sensitization.
PMID: 14522004 [PubMed - indexed for MEDLINE]
| 23: Brain Res. 2003 Aug 15;981(1-2):12-22. |