[Detection and Analysis of the peripheral lymphocytes micronucleus rate of radiation workers in a city].

Objective: To perform lymphocyte micronucleus analysis on radiation workers with long-term exposure to low doses ionizing radiation, Evaluate the health condition of radiation workers, and provide the evidence for strengthening surveillance of radiation workers. Methods: From January 1, 2013 to December 21, 2016, a statistical analysis and evaluation was conducted of the peripheral lymphocytes micronucleus rate in 5 901 radiation workers who had undergone medical examinations of employees at Chinese Academy of Medical Sciences Institute of Radiation Medicine. Results: The micronucleus rates in radiation workers of the on-job group were higher than the pre-job group (P<0.01) . Significant difference was found among the different sex (t=5.97) , different types (χ(2)=378.69) , different levels of work units (χ(2)=115.48) . Significant difference was found among the micronucleus rates of 672 radiation workers of the on-job group from 2013 to 2016 (χ(2)=92.57, P<0.01) . Conclusion: The peripheral lymphocytes micronucleus rate of radiation workers were significantly higher than non-contact workers. Significant increasing trend of micronucleus rates was noted among the radiation worker with increasing exposure time. The peripheral lymphocytes micronucleus rates of interventional therapy workers were highest. The peripheral lymphocytes micronucleus rates of Private hospitals workers were highest. This phenomenon deserves attention. Protection needs to be strengthened to ensure the health of radiation workers.

Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo.

Peptide nucleic acids (PNAs) form stable and tight complexes with complementary DNA and/or RNA and would be promising antisense reagents if their cellular delivery could be improved. We show that a 21-mer PNA, complementary to the human galanin receptor type 1 mRNA, coupled to the cellular transporter peptides, transportan or pAntennapedia(43-58), is efficiently taken up into Bowes cells where they block the expression of galanin receptors. In rat, the intrathecal administration of the peptide-PNA construct results in a decrease in galanin binding in the dorsal horn. The decrease in binding results in the inability of galanin to inhibit the C fibers stimulation-induced facilitation of the rat flexor reflex, demonstrating that peptide-PNA constructs act in vivo to suppress expression of functional galanin receptors.

Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered excitatory amino acid receptor antagonists.

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors.

We have previously reported that we have observed chronic pain-like response to light mechanical stimuli (allodynia) in rats after severe spinal cord ischemia, which resembles some painful conditions in chronic spinally injured patients and is not relieved by a number of conventional analgesics used for treating chronic neuropathic pain. In the present study, we tested the effects of the non-selective nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the selective neuronal NOS inhibitor 7-nitro indazole (7-NI) and 6-nitro indazole (6-NI) on the chronic allodynia-like behavior. Systemic L-NAME dose-dependently relieved mechanical allodynia-like response in a stereo-specific and L-arginine-reversible manner without causing sedation or motor deficits. However, L-NAME significantly elevated systemic blood pressure. Systemic 7-NI relieved chronic allodynia in a L-arginine reversible manner, did not increase blood pressure or induce sedation, but caused motor deficits at a high dose, which was not reversed by L-arginine. Systemic 6-NI also relieved the chronic allodynia, which was however associated with severe sedation. In order to exclude the possibility that the effect of L-NAME on blood pressure was involved in the analgesic effect observed, the effect of systemically applied adrenaline was examined. Adrenaline increased the systemic blood pressure to a similar extent as L-NAME, but did not relieve allodynia. It is suggested that blockade of NOS by L-NAME relieved the chronic allodynia-like behavior in spinally injured rats. This effect was likely to be mediated by a blockade of neuronal isoforms of NOS, as 7-NI relieved the allodynia in a L-arginine-reversible manner. Consequently, generation of NO by neuronal NOS may be critically involved in the maintenance of this abnormal pain-related sensation. The possibility of using NOS inhibitors as potential novel analgesics is discussed.

Treatment of chronic allodynia in spinally injured rats: effects of intrathecal selective opioid receptor agonists.

We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.

Possible impact of genetic differences on the development of neuropathic pain-like behaviors after unilateral sciatic nerve ischemic injury in rats.

The development of neuropathic-like behaviors following unilateral ischemic injury to the sciatic nerve was examined and compared in four rat strains: Sprague--Dawley (SD), Wistar--Kyoto (WK), spontaneously hypertensive (SHR) and Dark--Agouti (DA). We have also compared two sub-strains of SD rats supplied from two different vendors (SD-BK and SD-DK). The responses to mechanical, heat or cold stimuli of both hind paws were measured before and regularly after injury for up to 10 weeks. Spontaneous paw lifting and changes in paw posture after nerve injury were also examined. Significant differences in basal sensitivity to mechanical or heat stimulation were seen among the four rat strain studied with SHR and DA rats being less sensitive than the SD and WK rats. All strains of rats developed bilateral mechanical allodynia and ipsilateral heat hyperalgesia after photochemically-induced nerve ischemia, but the time-course and magnitude of the responses were significantly different among the strains. Again, the SHR and DA were found to be least susceptible to the development of abnormal pain-like responses. Cold allodynia occurred only in WK and SD-BK. SD-DK rats on the other hand developed more severe mechanical allodynia than SD-BK. SHR and DA rats showed less deficits in paw posture after nerve injury whereas spontaneous pain lifting, a measure of possible spontaneous pain, was comparable among all strains. Light microscopic study of the injured sciatic nerve showed comparable nerve damage in SHR, WK and two sub-strains of SD rats. The DA rats however exhibited reduced area of intraneural damage. Finally, electronmicroscopic examination revealed that damage to both myelinated and unmyelinated fibers occurred in this model in all strains. These results showed that normal sensitivity and the development of pain-like response after partial nerve injury differ substantially among different strains of rats, supporting the emerging concept that genetic factors affect pain sensitivity under normal conditions and after nerve injury. The apparent resistance of DA rats to nerve ischemia, however, may suggest that genetic factors not directly related to pain modulation also play a role in the diverse outcomes. Our results indicate that sub-strains of rats also showed variable development of neuropathic pain-like behaviors to both the modality and magnitude of the effect. Thus, controlling sub-strains is also important in experimental studies of neuropathic pain in rats.

Chronic pain-related syndrome in rats after ischemic spinal cord lesion: a possible animal model for pain in patients with spinal cord injury.

We examined a pain-related syndrome, which includes mechanical allodynia and autotomy, in rats after ischemic spinal cord injury photochemically induced by laser irradiation for 5-20 min. This procedure results in an acute allodynia-like phenomenon which lasts for several days and is possibly related to dysfunction of the GABAB system in the spinal cord. In some animals this is followed by a chronic allodynia-like symptom with an onset varying between 1 week and 1.5 months after injury, expressed as a clearly painful reaction to light pressure applied to a skin area at or near the dermatome of the injured spinal segments. In the majority of rats the allodynia persists over several months, in some cases accompanied by autotomy of the hind paws. Pharmacological studies indicated that the allodynia in the majority of rats could be relieved by systemic tocainide (75 mg/kg). Morphine was only effective at a sedative dose (5 mg/kg). The allodynia was not relieved by baclofen, muscimol, clonidine or carbamazepine. Low-dose systemic pentobarbital (5 mg/kg) had a slight beneficial effect. Guanethidine (20 mg/kg, s.c.) did not abolish the allodynia in most of the rats. Histological examination revealed massive damage in the spinal cord. The dorsal roots of the irradiated segments were also injured. No morphological abnormalities were seen in the dorsal root ganglia. The mechanism that may account for this chronic pain-related syndrome in spinally injured rats probably involves abnormalities in the central nervous system. The allodynia seen in chronic spinally injured rats was similar to some painful symptoms in patients after spinal cord injury or stroke. It is suggested that the chronic allodynia-like phenomenon may represent an animal model for studying the mechanisms of chronic central pain.

Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF.

Transcutaneous nerve stimulation (TENS) treatment was given for 30 min to 37 patients divided into 3 groups of 10 patients and 1 group of 7 patients. Two groups received low-frequency (2 Hz) and the other 2 groups high-frequency (100 Hz) stimulation. A diagnostic lumbar cerebrospinal fluid (CSF) sample was obtained immediately before and after stimulation. The CSF samples were subjected to analysis of immunoreactive (ir) opioid peptides, Met-enkephalin-Arg-Phe (MEAP) from preproenkephalin and dynorphin A (Dyn A) from preprodynorphin, respectively. Low frequency TENS applied on the hand and the leg resulted in a marked increase (367%, P less than 0.05) of ir-MEAP but not ir-Dyn A, whereas high-frequency (100 Hz) TENS produced a 49% increase in ir-Dyn A (P less than 0.01) but not ir-MEAP. This is the first report in humans that 2 Hz and 100 Hz peripheral stimulation induces differential release of peptides from preproenkephalin and preprodynorphin, respectively.

Long-term alleviation of allodynia-like behaviors by intrathecal implantation of bovine chromaffin cells in rats with spinal cord injury.

Adrenal chromaffin cells produce analgesic substances, such as catecholamines and enkephalins, and intrathecal (i.t.) implantation of either allografted adrenal tissue or xenogenic chromaffin cells produce antinociception in animals. We evaluated the analgesic effect of bovine chromaffin cells in a model of central pain in which rats exhibit chronic allodynia-like behavior after photochemically induced ischemic spinal cord injury. Bovine chromaffin cells or endothelial cells were injected i.t. onto the lumbar spinal cord and their effects on mechanical and cold allodynia-like behaviors were studied for up to 8 weeks. The chronic allodynia-like behavior was stable for months without signs of remission and i.t. implantation of human endothelial cells did not alleviate the chronic allodynia-like behavior for the entire observation period. In contrast, 2 weeks after i.t. implantation of bovine chromaffin cells, the mechanical allodynia was abolished in the spinally injured rats, and the enhanced response to cold stimuli was significantly reduced. The overall effects were significant up to 8 weeks after i.t. implantation, although the anti-allodynic effect decreased towards the end of the observation period. No signs of side-effects were noted after i.t. implantation. The allodynia-like state was temporarily restored by naloxone (0.5 mg/kg) or phentolamine (0.3 mg/kg) injected intraperitoneally. Immunohistochemical examination revealed that tyrosine hydroxylase (TH)-positive chromaffin cells could be identified adjacent to the spinal cord up to 4 weeks after i.t. implantation, whereas at 8 weeks the TH-positive cells were sparse. It is concluded that bovine chromaffin cells stay viable in rat spinal cord for a considerable period of time after i.t. administration and alleviate chronic allodynia-like behavior in spinally injured rats, possibly through activation of opioid and alpha-adrenoceptors. The present results further document a new therapeutic approach for the treatment of chronic neuropathic pain.

The effects of intrathecal neuropeptide Y on the spinal nociceptive flexor reflex in rats with intact sciatic nerves and after peripheral axotomy.

We examined the effects of intrathecally administered neuropeptide Y on the spinal nociceptive flexor reflex in decerebrate, spinalized, unanesthetized rats with intact sciatic nerves, or 11-39 days after unilateral transection of the sciatic nerve. In rats with intact sciatic nerve, intrathecal neuropeptide Y at low doses (10 and 100 ng) caused a brief facilitation of the flexor reflex. At a dose of 300 ng, the effect of neuropeptide Y on the flexor reflex was biphasic, i.e. a brief facilitation followed by slight depression. At higher doses (1 and 10 micrograms), the effect of neuropeptide Y was mainly inhibitory, causing substantial and usually prolonged depression of the flexor reflex magnitude. The reflex depression caused by intrathecal neuropeptide Y was not reversed by the opioid antagonist naloxone or the alpha 2 adrenoceptor antagonist atipamezole. Intrathecal neuropeptide Y at doses up to 1 and 10 micrograms had no effect on reflex facilitation caused by conditioning stimulation of C-fibers, intrathecal substance P or neurokinin A. Topical application of neuropeptide Y (1 microgram/microliter) failed to influence the monosynaptic reflex in normal rats. Eleven to 16 days after peripheral axotomy, the initial excitation of the flexor reflex to intrathecal neuropeptide Y was significantly enhanced in axotomized compared with normal rats. However, the depressive effect of neuropeptide Y on the flexor reflex was unchanged. Neuropeptide Y did not influence the monosynaptic reflex in axotomized rats at this period. In experiments performed on rats in which the sciatic nerve had been transected 31-39 days previously, the facilitatory effect of neuropeptide Y on the flexor reflex remained enhanced compared with normal rats. Furthermore, the inhibitory effect of neuropeptide Y also increased as 100 ng intrathecal neuropeptide Y was able to produce reflex depression in a similar fashion as 300 ng neuropeptide Y normally and the reflex depression caused by 1 microgram neuropeptide Y was stronger and longer lasting than in normal rats. Intrathecal neuropeptide Y (100 ng-10 micrograms) in rats with intact sciatic nerves caused a moderate decrease in spinal cord dorsal surface blood flow as measured with a laser Doppler flowmeter. This effect of neuropeptide Y was unchanged in axotomized rats. The present results support previous observations that spinal application of neuropeptide Y in normal rats caused antinociception. As the depressive effect of neuropeptide Y is independent of spinal opioid and alpha 2-adrenergic systems, it may be mediated by its own receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Spantide II, a novel tachykinin antagonist, and galanin inhibit plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw.

The effect of intradermal injection of Spantide II, a novel tachykinin antagonist, and the neuropeptide galanin on neurogenic plasma extravasation induced by antidromic stimulation of C-fibers in the sciatic nerve was examined in the hindpaws of rats. Activation of C-fibers by antidromic sciatic nerve stimulation (2 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans Blue in the skin area of the hindpaw innervated by the sciatic nerve. Intradermal injection of 3 nmol Spantide II significantly inhibited this response. The plasma extravasation was nearly totally abolished when the concentration of Spantide II was increased to 9 nmol. Intradermal injection of 1.5 and 15 nmol galanin also inhibited plasma extravasation. Intradermal injection of 9 nmol Spantide II effectively blocked the plasma extravasion in the hindpaw induced by 8 nmol intravenous substance P. Plasma extravasation induced by intravenous substance P was also inhibited by the higher, but not by the lower, dose of galanin injected intradermally. The present results indicate that Spantide II, a potent non-toxic tachykinin antagonist, effectively blocks the neurogenic plasma extravasation induced by antidromic C-fiber stimulation, thus supporting the view that tachykinins play an important role in this neurogenic inflammatory process. It is further shown that galanin, a naturally occurring neuropeptide present in primary afferents, also inhibits C-fiber activation-evoked plasma extravasation, indicating an interaction between galanin and tachykinins in the peripheral terminals of primary afferents, possibly through both pre- and postsynaptic mechanisms.

Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors.

Mice with a targeted disruption of adenosine A(3) receptor (A(3)AR) gene were assessed for their nociceptive threshold and for their localized inflammatory response following carrageenan injected into the hindpaw. Under basal conditions no difference was seen between A(3)AR knock-out (A(3)AR(-/-)) and wild-type (A(3)AR(+/+)) mice in nociceptive response to mechanical or heat stimuli. The antinociceptive response to the intrathecal adenosine analogue R-phenylisopropyl adenosine (R-PIA) was also unchanged in the A(3)AR(-/-) mice. In contrast, heat hyperalgesia, plasma extravasation and edema following carrageenan-induced inflammation in the hind paw were significantly reduced in A(3)AR(-/-) mice compared to the A(3)AR(+/+) controls. Thus, mice lacking A(3)AR had deficits in generating the localized inflammatory response to carrageenan, supporting a pro-inflammatory role of A(3)AR in peripheral tissues. However, no evidence for a role of A(3)AR in nociception and the antinociceptive effect of R-PIA was found.

Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.

Beneficial effect of the opioid receptor antagonist naltrexone on hyper-sensitivity induced by spinal cord ischemia in rats: disassociation with MK-801.

In this study we examined the effect of the long-acting opioid antagonist naltrexone on the allodynia-like effect of spinal ischemia in rats. The spinal cord ischemia was induced at midthoracic level by a recently developed photochemical technique using laser irradiation and photoactivatable intravascular dyes. An allodynia-like sensory disturbance, where the animals reacted by vocalization to non-noxious mechanical stimuli in the flank area, was consistently seen during several days after ischemia. Pretreatment with 10 and 20 mg/kg, but not 5 mg/kg naltrexone i.v. 10 min before irradiation decreased the incidence of allodynia. However, even the effect of the highest dose of naltrexone (20 mg/kg) was incomplete, which is in contrast to the effect of the NMDA receptor antagonist MK-801, which has been tested in the same model and found to completely prevent the incidence of allodynia at a dose of 0.5 mg/kg. Pretreatment with sub- or suprathreshold doses of naltrexone (5 and 20 mg/kg respectively) combined with a subthreshold dose of MK-801 (0.1 mg/kg) did not produce a synergistic effect. When naltrexone (20 mg/kg) was administered 10 min after induction of ischemia, it was totally ineffective in decreasing the occurrence and severity of allodynia. In contrast, MK-801 (0.5 mg/kg) still had a good protective effect when injected as this time. Histological examination showed slight morphological damage in the spinal cord in 38% of control rats after 1 min laser irradiation without pretreatment with naltrexone. No morphological abnormalities were observed in rats after pretreatment with naltrexone (20 mg/kg). The results suggest that opioid receptor antagonists and NMDA receptor antagonists prevent a consequence of transient spinal cord ischemia through different mechanisms. High doses of opioid antagonists may have anti-ischemic effects by improving local spinal cord microcirculation and therefore may have a role in preventing ischemia after traumatic spinal cord injury. On the other hand, the NMDA receptor may have a role in the secondary neuronal death resulting from ischemia. Thus, NMDA receptor antagonists may contribute to the prevention of tissue damage by antagonizing the excitotoxic action of glutamate and/or aspartate released by ischemia into the spinal cord. Finally, since only high doses of naltrexone had an effect in the present study, we cannot rule out the possiblity that this drug may act through non-opioid mechanisms.

Nociceptin or antinociceptin: potent spinal antinociceptive effect of orphanin FQ/nociceptin in the rat.

A heptadecapeptide (orphanin FQ or nociceptin) was recently identified as an endogenous ligand for the orphan opioid-like receptor. Here we report that intrathecal orphanin FQ produces dose-dependent depression of a spinal nociceptive flexor reflex in the rat. Furthermore, administration of orphanin FQ in rats with intrathecal catheters produced behavioural antinociception in the tail flick test with no signs of sedation or motor impairment. The reflex depressive effect of orphanin FQ was not reversed by antagonists of opioidergic, alpha 2-adrenergic and GABA-A receptors. Thus, orphanin FQ may suppress nociceptive input at the spinal level through an novel mechanism. Orphanin FQ or agonists of its receptor may represent novel analgesics for pain conditions which are not responsive to existing pharmacological therapy.

Intrathecal adenosine does not relieve allodynia-like behavior in spinally injured rats.

The intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral nerve or spinal cord injury in rats. The endogenous ligand adenosine is clinically available and has been tested i.t. as an analgesic. Thus, we set out to investigate whether i.t. adenosine could reduce allodynia in a model of central pain in spinally injured rats. I.t. adenosine did not reduce mechanical and cold allodynia-like behaviors at doses of 10, 100 and 187 nmol, whereas i.t. R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic reasons. Alternatively, adenosine may have reduced affinity and selectivity towards the A1-receptors which may be important for the antiallodynic effect.

Spinal cord ischemia reduces mu-opioid receptors in rats: correlation with morphine insensitivity.

The present study examined the effects of spinal cord ischemia on the expression of mu-opioid receptors in rat dorsal spinal cord and the effects of intrathecal (i.t.) morphine on the acute mechanical allodynia that developed after spinal ischemia. The mechanical allodynia was not significantly alleviated by up to 10 microg i.t. morphine, a dose which caused strong antinociception in the tail flick test. Immunohistochemical staining demonstrated that the level of mu-opioid receptor expression in the dorsal horn of spinal cord segments receiving input from the allodynic skin was markedly reduced 2 days after ischemia, when the rats were allodynic. The results indicate that spinal cord ischemia reduces the expression of mu-opioid receptors in rat dorsal horn, which may be one of the underlying mechanisms of morphine insensitivity for treating acute allodynia after spinal ischemia.

Interferon-gamma receptors in nociceptive pathways: role in neuropathic pain-related behaviour.

Interferon-gamma receptor (IFN-gamma R) immunoreactivity was observed in the superficial dorsal horn and lateral spinal nucleus in rat and mouse spinal cord. Dorsal rhizotomies did not reduce immunoreactivity in the rat. IFN-gamma R distribution overlapped with nitric oxide synthase-1 immunoreactivity. In wild-type mice, intrathecal injections of mouse IFN-gamma evoked biting behaviour, whereas mice with disruption of the functional gene for IFN-gamma R did not respond. Both types of mice had similar withdrawal thresholds to mechanical stimulation and reacted similarly to foot-pad carrageenan injections. In contrast to wild-type mice, IFN-gamma R knock-out mice did not show autotomy after sciatic nerve section. This study demonstrates a functional IFN-gamma R in spinal nociceptive pathways related to neuropathic pain.

Mice over-expressing galanin have elevated heat nociceptive threshold.

The neuropeptide galanin may have a role in modulation of nociceptive input at spinal level. Here we report that mice over-expressing galanin exhibit significant elevation of nociceptive threshold to thermal stimulation in comparison to wild-type mice as assessed by the tail flick and paw heat irradiation tests. No change in response to mechanical or cold stimulation was seen. The elevated heat nociceptive threshold in the galanin over-expressing mice was reversed by intrathecal application of the putative galanin receptor antagonist M-35, galanin-(1-12)-pro-bradykinin-(2-9). The results thus support that galanin has an inhibitory function in rodent spinal cord.

Increased level of cholecystokinin in cerebrospinal fluid is associated with chronic pain-like behavior in spinally injured rats.

Cholecystokinin (CCK) is a physiological antagonist of opioid-mediated antinociception and may be involved in some chronic pain states where opioids have reduced effect. We have previously shown in a rat model of central neuropathic pain after spinal cord injury that blockade of CCK-B receptors lead to marked pain relief. In the present study, we showed that spinally injured rats exhibiting chronic pain-like behaviors (aversive reaction to innocuous mechanical and cold stimulation) had significantly elevated level of CCK-like immunoreactivity in cerebrospinal fluid compared to normal rats or spinally injured rats which did not exhibit pain-like behaviors. The increased level of circulating CCK in the cerebrospinal fluid may thus contribute to the maintenance of chronic pain in these rats by reducing the endogenous inhibitory tone provided by opioid peptides and may be involved in the phenomenon of opioid insensitivity.