[show abstract][hide abstract] ABSTRACT: In this work, we described a method of testing of responses of spinally injured rats to thermal stimulation (heating and cooling) to the flank area using a Peltier thermode. With a baseline holding temperature at 32°C and the temperature change rate of 0.5°C/s, we measured vocalization thresholds of rats to thermal stimulation in the flank area. While normal rats did not vocalize to temperatures changes ranging from 6°C to 50°C, the spinally injured rats exhibited significantly increased response to cooling with average response temperature above 15°C through the 70 day observation period after spinal cord injury. The response temperature to cooling in spinally injured rats is correlated with the magnitude of responses to cold stimulation scored after ethyl chloride spray and with the response threshold to mechanical stimulation. In contrast, we did not observe an increase in response to warm/heat stimuli. The results showed that ischemic spinal cord injury produced cold, but not heat, allodynia in rats. Furthermore, we showed that it is possible to quantitatively measure response of rats to thermal stimulation on the body using temperature as end points which may aid further studies on mechanisms and treatments of thermal stimulation, particularly cold, evoked pain.
Journal of neuroscience methods 11/2012; · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neuropathic pain is caused by a lesion or disease to the somatosensory nervous system and current treatment merely reduces symptoms. Here, we investigate the potential therapeutic effect of the neurotrophic factor Meteorin on multiple signs of neuropathic pain in two distinct rat models. In a first study, two weeks of intermittent systemic administration of recombinant Meteorin led to a dose-dependent reversal of established mechanical and cold hypersensitivity in rats after photochemically-induced sciatic nerve injury. Moreover, analgesic efficacy lasted for at least one week after treatment cessation. In rats with a chronic constriction injury (CCI) of the sciatic nerve, five systemic injections of Meteorin over 9days dose-dependently reversed established mechanical and thermal hypersensitivity as well as weight bearing deficits taken as a surrogate marker of spontaneous pain. The beneficial effects of systemic Meteorin were sustained for at least three weeks after treatment ended and no adverse side effects were observed. Pharmacokinetic analysis indicated that plasma Meteorin exposure correlated well with dosing and was no longer detectable after 24hours. This pharmacokinetic profile combined with a delayed time of onset and prolonged duration of analgesic efficacy on multiple parameters suggests a disease-modifying mechanism rather than symptomatic pain relief. In sciatic nerve lesioned rats, delivery of recombinant Meteorin by intrathecal injection was also efficacious in reversing mechanical and cold hypersensitivity. Together, these data demonstrate that Meteorin represents a novel treatment strategy for the effective and long lasting relief from the debilitating consequences of neuropathic pain.
[show abstract][hide abstract] ABSTRACT: Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.
[show abstract][hide abstract] ABSTRACT: Neuropathic pain after injury to the nervous system is a difficult clinical problem. Sex differences in the development of neuropathic pain have not been well established experimentally or clinically.
Rats were used to examine sex differences in localized and spread mechanical hypersensitivity after partial injury to their infraorbital or sciatic nerves in a model of neuropathic pain.
In adult female and male rats, partial nerve injury to the infraorbital and sciatic nerves was produced using a photochemical method. Mechanical hypersensitivity (allodynia) was examined and compared in the innervation territories of the nerves on the face or hind paw. The spread of hypersensitivity beyond the innervation territories of the injured nerves was also studied. The female and male rats were randomized to active and sham groups. The rats in the sham group had their sciatic or infraorbital nerve exposed, but not injured.
A total of 67 rats (36 females, 31 males) were used. There was a marked sex difference in the response to infraorbital nerve injury: female rats developed more profound and long-lasting facial hypersensitivity than did male rats (P<0.001). Hypersensitivity of the hind paw after sciatic nerve injury did not, however, significantly differ between female and male rats. Spread mechanical hypersensitivity was noted in body areas outside the innervation territory of the injured nerve. This hypersensitivity was more profound after infraorbital than sciatic nerve injury and also displayed a significant sex difference (female>male, P < 0.001). Sham-group rats did not exhibit localized or spread mechanical hypersensitivity.
Sex differences in the development of neuropathic painlike behaviors in rats were dependent on site of injury and site of testing, with female rats being more susceptible to the development of spread mechanical hypersensitivity, particularly after facial nerve injury, compared with male rats.
Gender Medicine 01/2009; 6 Suppl 2:225-34. · 1.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neuropathic pain is a common consequence of damage to the nervous system. We here report a genetic analysis of development of neuropathic pain-like behaviors after unilateral photochemically-induced ischemic sciatic nerve injury in a panel of inbred rat strains known to display different susceptibility to autoimmune neuroinflammation. Pain behavior was initially characterized in Dark-Agouti (DA; RT1(av1)), Piebald Virol Glaxo (PVG; RT1(c)), and in the major histocompatibility complex (MHC)-congenic strain PVG-RT1(av1). All strains developed mechanical hypersensitivity (allodynia) following nerve injury. However, the extent and duration of allodynia varied significantly among the strains, with PVG displaying more severe allodynia compared to DA rats. Interestingly, the response of PVG-RT1(avRT1) was similar to that of DA, suggesting regulation by the MHC locus. This notion was subsequently confirmed in an F2 cohort derived from crossing of the PVG and PVG-RT1(av1)strains, where allodynia was reduced in homozygous or heterozygous carriers of the RT1(av1) allele in comparison to rats homozygous for the RT1(c) allele. These results indicate that certain allelic variants of the MHC could influence susceptibility to develop and maintain neuropathic pain-like behavior following peripheral nerve injury in rats.
[show abstract][hide abstract] ABSTRACT: The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. Administration of lacosamide twice daily at 20 mg/kg for 7 days totally alleviated the allodynia-like state in spinally-injured rats with no tolerance. Following treatment cessation the cold and the static allodynia reappeared but the effect on dynamic mechanical allodynia (brushing) was maintained until day 11. Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.
European Journal of Pharmacology 01/2007; 553(1-3):135-40. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development.
[show abstract][hide abstract] ABSTRACT: We used a photochemical method to generate a partial ischemic injury to the infraorbital branch of the trigeminal nerve in rats. Following injury, rats developed a bilateral persistent hypersensitivity to mechanical stimulation in the territory innervated by the infraorbital nerve. In addition, spread of mechanical hypersensitivity beyond the facial region was noted. Heat hypersensitivity was also present, although to a lesser extent and of a shorter duration. In some rats, excessive facial grooming/scratching were observed. Morphological examination revealed a graded damage to the irradiated portion of the infraorbital nerve that was related to the duration of laser irradiation. Investigations of gene expression changes in injured trigeminal ganglion neurons of animals with behavioral signs of neuropathic pain demonstrated that the sodium channel alpha-subunit Na(v)1.3-absent in sham-operated animals-was expressed to a limited extent. mRNAs for Na(v)1.8 and Na(v)1.9 were reduced both with respect to proportions of expressing neurons and to intensities, whereas the beta 3 subunit was markedly upregulated. mRNA levels of p11, a regulatory factor that facilitates the surface expression of Na(v)1.8, were unchanged. Previous findings have shown that injury to the trigeminal nerve branches may elicit responses that differ from those of segmental spinal nerves. Despite this we conclude that the key sodium channel regulations that are reported as consequences of nerve damage in the dorsal root ganglia seem to appear also in the trigeminal ganglion. Thus, novel analgesic drugs designed to target the sodium channel subtypes involved could be of use for the treatment of orofacial pain.
[show abstract][hide abstract] ABSTRACT: Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the mu-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6mg/kg) and methadone (3mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5h post-injection (P<0.05); codeine (30mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6mg/kg) and methadone (0.5-3mg/kg) robustly attenuated mechanical and cold allodynia for at least 2h post-injection (P<0.05). Codeine (10 and 30mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of mu-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.
[show abstract][hide abstract] ABSTRACT: The role of the adenosine A1 receptor in nociception was assessed using mice lacking the A1 receptor (A1R-/-) and in rats. Under normal conditions, the A1R-/- mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1R+/+). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1R-/- mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the mu-opioid ligand DAMGO in the spinal cord. A1R-/- mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1R-/-mice. Peripheral nerve injury did not change the level of adenosine A1 receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the adenosine A1 receptor plays a physiological role in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.
[show abstract][hide abstract] ABSTRACT: The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. Here we assessed the development of neuropathic pain-like behaviors in mice overexpressing galanin under the dopamine beta-hydroxylase promoter. Unoperated galanin over-expressing mice exhibited a moderately reduced sensitivity to noxious heat. Both galanin over-expressing mice and wild-type controls developed mechanical and heat hypersensitivity after photochemically induced partial sciatic nerve ischemic injury. The magnitude and persistence of such pain-like behaviors were significantly less, and recovery was faster in galanin over-expressing mice compared to wild types. However, the recovery from toe-spread deficits did not differ between galanin over-expressing and wild-type mice after a crush injury to the sciatic nerve. Thus, early recovery in pain-like response is unlikely to result from accelerated regeneration in the galanin over-expressing mice. Immunohistochemical analysis showed that galanin is over-expressed both in small and large dorsal root ganglion cells in the transgene mouse, whereas large galanin-positive neurons were never seen in wild-type mice. The present results in general support an inhibitory role of galanin in nociception and indicate that increased availability of galanin in spinal dorsal horn at the time or shortly after nerve injury may reduce the development of pain-like behaviors in mice.
Brain Research 11/2004; 1025(1-2):152-8. · 2.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: The physiological mechanisms of chronic pain in patients with spinal cord injury (SCI) are poorly understood. In the present study, we explored response characteristics of dorsal horn neurons of spinally injured rats exhibiting chronic pain (pain-like response to innocuous mechanical and cold stimulation). Several abnormalities were found in the distribution and response characteristics of dorsal horn neurons in chronic allodynic rats. First, 17% of the recorded neurons (vs. 0% in control animals) had no receptive field. Most of these units were located at or close to the lesioned spinal segment, and they discharged spontaneously at high frequencies. Allodynic rats also showed a significant decrease in the proportion of low-threshold (LT) neurons and an increase in the proportion of wide dynamic range (WDR) neurons. The rate of spontaneous activity of high-threshold (HT) neurons was significantly higher in allodynic compared with control rats. Moreover, HT neurons in allodynic animals showed increased neuronal responses to mechanical stimulation. WDR neurons responded with higher discharge rates to innocuous von Frey hair stimulation in allodynic compared with control rats. The percentage of WDR and HT neurons showing afterdischarges to noxious pinch was also significantly increased in the allodynic rats. The proportion of WDR and HT neurons responding to innocuous cold stimulation respectively increased from 53 and 25% in control rats to 91 and 75% in allodynic animals. These results suggest that the chronic pain-like behaviors in spinally injured rats may be generated and maintained by abnormalities in dorsal horn neurons.
Journal of Neurophysiology 10/2004; 92(3):1391-9. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.
European Journal of Pharmacology 09/2004; 497(1):29-33. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: A simple method for chronic intrathecal (i.t.) catheterization of the lumbar subarachnoid space in mice is described. The procedure does not require major surgery and does not produce neurological deficits. The intrathecal catheter stayed in place and was functional for at least 10 days. Morphological studies revealed no histological damage in the spinal cord after catheter implantation. The effects of acute and chronic intrathecal morphine were studied and compared between the current method and that of acute lumbar puncture. Morphine produced similar antinociceptive effect when administered acutely. All mice with catheters responded reliably to daily morphine injection up to 5 days whereas it was difficult to inject drugs repeatedly with lumbar puncture. It is concluded that this novel method of chronic lumbar catheterization in mice has advantages over the existing lumbar puncture technique for intrathecal delivery of drugs upon repeated administration. This method may be particularly useful in studies of genetically modified mice where the number of mice available is often limited.
Journal of Neuroscience Methods 03/2004; 133(1-2):65-9. · 2.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: 1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.
British Journal of Pharmacology 02/2004; 141(1):65-74. · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have examined the effect of systemically administered galnon, a novel low-molecular weight agonist of galanin receptors, on neuropathic pain-like behaviors in rats after photochemically induced partial nerve injury. Galnon is a galanin receptor ligand with moderate affinity to spinal cord membranes (K(D) of 6+/-0.6 microM). While intraperitoneally applied galnon produced no significant effect on mechanical or cold hypersensitivity, it dose-dependently prolonged heat withdrawal latency in nerve-injured rats. The effect of galnon was more potent on the injured side which has significantly shorter latency than the contralateral side. The anti-hyperalgesic effect of galanon was prevented by intrathecal M35, a galanin receptor antagonist. No side effects, such as sedation or motor impairment, were seen following systemic galnon treatment at the doses used. It is concluded that systemic galnon alleviated heat-hyperalgesic response in rats with partial sciatic nerve injury. This effect was likely to be mediated by activation of spinal galanin receptors.
European Journal of Pharmacology 01/2004; 482(1-3):133-7. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Central neuropathic pain after spinal cord injury (SCI) presents a challenging clinical problem with limited treatment options. [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]]-methadone (F 13640) is a recently discovered very-high-efficacy, selective 5-HT1A receptor agonist that produces a remarkably powerful, central analgesia through unprecedented neuroadaptive mechanisms. In a rat model of spinal cord injury pain, we previously found that chronic infusion of F 13640 alleviated pain-like behaviors. Here, we report that infusion of 0.63 mg/day of F 13640 for 8 weeks starting 24 h before the induction of injury significantly attenuates the development of chronic allodynia-like behavior in rats sustaining a photochemically-induced, ischaemic injury of the dorsal laminae of the L3-L5 segments of the spinal cord. Importantly, the preemptive effect of F 13640 persisted for 2 months after treatment was discontinued. The data warrant the study of the possible effects of the early administration of F 13640 in patients sustaining spinal cord injury.
European Journal of Pharmacology 10/2003; 478(2-3):131-7. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with spinal cord injury often develop chronic pain syndrome, which is difficult to treat. Several animal models of spinal cord injury have been developed in recent years which have significantly advanced our understandings of pathophysiology of this condition. This paper reviews some recent data in the pharmacological treatment of spinal cord injury pain using animal models, and discusses possible clinical applications.
Journal of Rehabilitation Medicine 06/2003; · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pain-relieving effects of various voltage-activated Na(+) channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. However, lamotrigine (10, 30 and 60 mg/kg) significantly attenuated mechanical hyperalgesia in the spared nerve injury model, while mexiletine (25 and 37.5 mg/kg, i.p.) attenuated mechanical allodynia in the Gazelius model. Tocainide (50, 75 and 100 mg/kg, i.p.) significantly reduced all types of pain behaviour measured. The present results show that these voltage-activated Na(+) channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.
European Journal of Pharmacology 02/2003; 458(3):275-82. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have studied and compared the antinociceptive and anti-hyperalgesic effect of the partial opioid receptor agonist buprenorphine in normal and neuropathic rats. In normal rats, systemic buprenorphine produced dose-dependent antinociception on the hot plate test. In rats with peripheral nerve or spinal cord injury, buprenorphine markedly alleviated neuropathic pain-related behaviors, including mechanical and cold allodynia/hyperalgesia at doses comparable to that producing antinociception. The results suggest that buprenorphine may be a useful analgesic for treating neuropathic pain and thus is an atypical opioid since morphine tends to be less potent after nerve injury.
European Journal of Pharmacology 09/2002; 450(1):49-53. · 2.59 Impact Factor