Young Wook Yoon

Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats

This study examined whether or not the production of mechanical allodynia in a rat model of neuropathic pain required an involvement of supraspinal site(s). To this aim, we assessed the effect of spinal cord section at the L1 segment level on the mechanical allodynia sign (i.e. tail flick/twitch response), which was elicited by innocuous von Frey hair stimulation of the tail after unilateral transection of the tail-innervating nerve superior caudal trunk (SCT) at the level between the S3 and S4 spinal nerves. Cord transection or hemisection of the cord ipsilateral to the injured SCT drastically (though not completely) blocked the behavioral sign of mechanical allodynia (leaving noxious pinprick-elicited tail withdrawal reflex intact), whereas sham section or contralateral hemisection of the cord was without effect. These results suggest that the generation of mechanical allodynia following partial peripheral nerve injury involves transmission of the triggering sensory signal to a site(s) rostral to the L1 segment via an ipsilateral pathway(s).

A novel method for convenient assessment of arthritic pain in voluntarily walking rats

Quantification of arthritic pain can be very useful in elucidating the mechanisms of arthritis and in assessing the effect of anti-arthritic medication or treatment. Here we report a novel method that allows convenient measurements of the severity of arthritic pain in voluntarily walking rats. We constructed a device to measure the weight load on each leg while the animal was walking through a path, the bottom of which was equipped with strain gauge weight sensors. Using this device, we measured the weight load on the right hind leg before and after induction of arthritis by carrageenan injection into the knee joint cavity of this leg. The carrageenan injection resulted in a significant reduction of weight load on the affected leg; the load decreased to the minimum level at 4 h after the injection and gradually returned to the pre-injection level by the fifth day. Intraperitoneal administration of morphine at 5.5 h after carrageenan injection could reverse the weight load change. These results suggest that our new device is an effective tool for convenient measurements of arthritic pain in dynamic conditions like walking.

Mechanical allodynia is more strongly manifested in older rats in an experimental model of peripheral neuropathy

Partial peripheral nerve injury often leads to chronic neuropathic pain characterized by symptoms such as allodynia. In the present study, employing a rat model of experimental neuropathy produced by partial denervation of the tail, we examined whether peripheral nerve injury-induced mechanical and thermal allodynia were affected by the animals age at the time of the injury. The motive of this study was the demonstration in other neuropathy models of the age effects on the manifestation of neuropathic pain symptoms following partial peripheral nerve injury. We compared two groups of young (n = 23, 7-8 weeks old, 150-200 g) and old rats (n = 14, 16-18 months old, 550-800 g). We found that the older rats exhibited more vigorously the behavioral signs of mechanical allodynia during the first week after the nerve injury. With respect to thermal (cold or warm) allodynia, however, we detected no significant difference between young and old rat groups. The results of the present study, as those of previous studies, support the idea that the age at the time of partial peripheral nerve injury affects the severity of certain neuropathic pain symptoms appearing after the injury. However, the present results argue against the suggestion from previous studies that younger subjects are more vulnerable to partial peripheral nerve injury-induced neuropathic pain symptoms.

Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models

Summary NR2B antagonists increased the mechanical nociceptive threshold after 2 experimental spinal cord injury models with no motor depression, and NR2B expression was increased in the spinal cord. ABSTRACT N‐Methyl‐D‐aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000 nmol) and Ro25‐6981 (20, 50, 100, 200 nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25‐6981 increased the mechanical nociceptive threshold in a dose‐dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1–2 and L4–5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.

Re: “Kinesio Taping Improves Pain, Range of Motion, and Proprioception in Older Patients with Knee Osteoarthritis: A Randomized Controlled Trial”

Objective This study investigated the short-term effects of Kinesio taping (KT) on various types of pain, active range of motion (AROM), and proprioception in patients with knee osteoarthritis. Design Forty-six older participants (mean [SD], 57.9 [4.4] yrs) with osteoarthritis were randomly allocated to two groups: the KT group or the placebo-KT group. Taping with tension (KT application) or without tension (placebo-KT application) was applied to the quadriceps of the participants in both groups. Before and after intervention, pain intensity was measured using a visual analog scale at rest and during walking, and pressure pain thresholds (PPTs) were assessed using an algometer in the quadriceps and the tibialis anterior. In addition, pain-free AROM and proprioception were measured. Results The KT group showed attenuation of pain during walking (effect size [ES], 1.97), PPT in the quadriceps (ES, 2.58), and PPT in the tibialis anterior (ES, 2.45). This group also showed significantly improved AROM (ES, 2.01) and proprioception (ES, 1.73–1.89; P < 0.05). However, the placebo-KT group did not show significant changes in pain, AROM, or proprioception. There were significant differences between the two groups in pain during walking and PPT. In addition, pain during walking showed a significant correlation with AROM and proprioception, and a significant correlation was found between PPT and AROM. Conclusions These results demonstrated that KT application with proper tension to the quadriceps effectively attenuates various types of pain and improves AROM and proprioception in osteoarthritis patients. Thus, KT may be a suitable intervention to improve pain, AROM, and proprioception in patients with osteoarthritis in clinics.

Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat

Substance P is known to exert various pro-inflammatory effects that are mediated by neurokinin-1 (NK-1) receptor in peripheral tissues. This study examined the effect of the NK-1 receptor antagonist cis-2-[diphenylmethyl]-N-[(2-iodophenyl)-1-azabicyclo[2.2.2]octan-3-amine] (L-703,606) on nociceptive response following carrageenan injection (2%, 50 microl) into the knee joint cavity of the right hind leg. L-703,606 injection (0.1 or 1 mM, 50 microl) into the same joint cavity immediately before the carrageenan injection significantly reduced the nociceptive response. However, antagonist treatment at 5 h after carrageenan injection was ineffective in alleviating nociception. Neither intraperitoneal injection of the antagonist (1 mM, 50 microl) immediately before the carrageenan injection was effective. These results suggest that local NK-1 receptor contributes to the induction, but not maintenance, of arthritic pain.

The peripheral role of group I metabotropic glutamate receptors on nociceptive behaviors in rats with knee joint inflammation

We examined whether the mGluR1 and mGluR5 were involved in development and maintenance of behavioral signs of non-evoked pain and secondary mechanical hyperalgesia induced by knee joint inflammation. Selective mGluR1 antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA: 50, 100, 200 microM/25 microl, n=10 per group) and selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP: 50, 100, 200 nM/25 microl, n=10 per group) was intra-articularly (i.a.) injected 30 min before and 4h after carrageenan injection and behavioral tests were conducted. In the pre-treatment, only a higher dose (200 nM) of MPEP significantly prevented the magnitude of weight load reduction, whereas AIDA (200 microM) and MEPE (50, 100 and 200 nM) significantly reduced the development of mechanical hyperalgesia compared to saline treated group. In the post-treatment, AIDA (200 microM) and MPEP at 100 and 200 nM partially reversed the reduction of weight load induced by carrageenan. MPEP significantly increased the withdrawal threshold to mechanical stimulation in a dose-dependent manner, whereas AIDA had significantly reversed the decreased the paw withdrawal threshold only at 200 microM. The present study demonstrated that i.a. MPEP, selective mGluR5 antagonist is more effective than selective mGluR1 antagonist, AIDA on non-evoked pain as well as mechanical hyperalgesia in both induction and maintenance phase in knee joint inflammation. It is suggested that peripheral mGlu5 receptors play a more prominent role in inflammatory pain including evoked and spontaneous pain. Thus, selective mGluR5 antagonist could be effective therapeutic tools in clinical setting.

The glutamatergic N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the joint contribute to the induction, but not maintenance, of arthritic pain in rats

To determine whether both the N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the knee joint contribute to the induction and/or maintenance of arthritic pain, we examined the effects of intra-articular injection of NMDA receptor antagonist dizocilpine (MK-801) and non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) on the decrease in weight load induced by carrageenan injection into the knee joint cavity in rats. Injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.25, 0.625 and 2.5 mM) immediately prior to carrageenan injection (2%, 40 microl) significantly prevented the pain-related behavior. However, injection of MK-801 (0.75 and 1.5 mM) and NBQX (0.625 and 2.5 mM) 5 h after carrageenan injection had no effect on pain-related behavior. These results suggest that both the NMDA and non-NMDA receptors in the knee joint are involved in the induction, but not maintenance, of arthritic pain.

Cold and mechanical allodynia in both hindpaws and tail following thoracic spinal cord hemisection in rats: time courses and their correlates

We assessed (1) the time courses of cold and mechanical allodynia in both hindpaws and the tail, and (2) the relationship of the allodynia signs between different sites following spinal cord hemisection. Under enflurane anesthesia, rats were subjected to spinal hemisection at T13. The hemisected rats exhibited a significant increase in mechanical and cold allodynia signs of both hindpaws and the tail for 22-26 weeks postoperatively. In addition, mechanical allodynia signs were significantly correlated not only between the ipsilateral and the contralateral hindpaws, but also between the hindpaws and the tail. These results suggested that cold and mechanical allodynia developed extensively and lasted for a long time following spinal cord hemisection, and mechanical allodynia shown at different sites may be induced at least in part by common generating mechanisms.

Intramuscular administration of morphine reduces mustard oil‐induced craniofacial muscle pain behavior in lightly anesthetized rats

The present study investigated the role of peripheral opioid receptors in mustard oil‐induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague–Dawley rats weighing between 300 and 400g. After initial anesthesia with sodium pentobarbital (40mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30μl) was injected into the mid‐region of the left masseter muscle via a 30‐gauge needle. Intramuscularly‐administered morphine significantly reduced shaking behavior but not MO‐induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly‐administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d‐Pen‐Cys‐Tyr‐d‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2 (CTOP), a μ opioid receptor antagonist, but not naltrindole, a δ opioid receptor antagonist, nor norbinaltorphimine (nor‐BNI), a κ opioid receptor antagonist, reversed intramuscularly‐administered morphine‐induced antinociception. These results indicate that intramuscularly‐administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly‐administered morphine‐induced antinociception is mediated by a peripheral μ opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.