Formalin-induced Pain Behavior Research Articles

Receptors and channels: Blunted formalin-induced pain behavior and spinal c-fos expression in mice lacking Chapsyn-110/PSD-93

Receptors and channels: Blunted formalin-induced pain behavior and spinal c-fos expression in mice lacking Chapsyn-110/PSD-93

Effects of long-term exposure of lemon essential oil odor on behavioral, hormonal and neuronal parameters in male and female rats

Behavioral, hormonal and neuronal responses to prolonged exposure to the volatile components of essential oil (EO) extracted from citrus lemon were investigated in male and female rats. Animals were exposed to the lemon essence for 2 weeks while in their cage. Anxiety was then determined with the elevated plus-maze apparatus while nociception was evaluated with a phasic thermal pain stimulus (plantar test) and with a chemical pain stimulus (formalin test). At the end of the experimental sessions, brain areas were dissected to measure β-endorphin (β-EP) concentrations in the hypothalamus and periaqueductal gray matter (PAG). Blood samples were collected to determine corticosterone plasma levels. In both sexes, prolonged EO exposure decreased the time spent in the open arms of the plus-maze apparatus. EO-exposed males and females showed higher thermal nociceptive thresholds than controls when tested with the plantar test apparatus. EO exposure induced female-specific decreases in formalin-induced pain behaviors during the formalin test. β-EP concentrations in the hypothalamus and PAG were affected by EO. Corticosterone was lower in EO-exposed animals of both sexes than in their controls. These results suggest that long-term exposure to lemon EO can induce significant, at times sex-specific, changes in neuronal circuits involved in anxiety and pain.

Role of μ-opioid receptors in formalin-induced pain behavior in mice

Intraplantar formalin injection is widely used as an experimental model of tonic pain. We investigated the role of endogenous μ-opioid receptor mechanisms in formalin-induced nocifensive behavior in mice. The flinching response induced by formalin (2%, 20 μl) was studied in mice with normal (wild type, n = 8) and absent (homozygous μ-opioid receptor knockout, n = 8) μ-opioid receptor levels. The flinch responses were counted every 5 min for 60 min post-formalin injection. Lumbar spinal cord (L4, 5) was harvested 2 h post-formalin injection to examine c-Fos expression using immunohistochemistry. The effects of naloxone (5 mg/kg, sc) administered 30 min before the intraplantar formalin injection on the flinching response of wild-type mice ( n = 7) were also recorded. The second-phase formalin response (10–60 min after formalin) was higher in homozygous μ-opioid receptor knockout mice compared to the wild-type mice ( P < 0.01). Naloxone administration in wild-type mice before formalin injection resulted in pain behavior similar to that observed in homozygous μ-opioid receptor knockout mice ( P > 0.05). The c-Fos expression induced by formalin injection in the knockout mice was not different from that observed in wild-type mice. Our results suggest that the endogenous μ-opioid system is activated by intraplantar formalin injection and exerts a tonic inhibitory effect on the pain behavior. These results suggest an important modulatory role of endogenous μ-opioid receptor mechanisms in tonic pain states.

Role of Thalamic Phospholipase Cβ4 Mediated by Metabotropic Glutamate Receptor Type 1 in Inflammatory Pain

Phospholipase C (PLC) beta4, one of the four isoforms of PLCbetas, is the sole isoform expressed in the mouse ventral posterolateral thalamic nucleus (VPL), a key station in pain processing. The mouse thalamus also has been shown to express a high level of metabotropic glutamate receptor type 1 (mGluR1), which stimulates PLCbetas through activation of Galphaq/11 protein. It is therefore expected that the thalamic mGluR1-PLCbeta4 cascade may play a functional role in nociceptive transmission. To test this hypothesis, we first studied behavioral responses to various nociceptive stimuli in PLCbeta4 knock-out mice. We performed the formalin test and found no difference in the pain behavior in the first phase of the formalin test, which is attributed to acute nociception, between PLCbeta4 knock-out and wild-type mice. Consistent with this result, acute pain responses in the hot plate and tail flick tests were also unaffected in the PLCbeta4 knock-out mice. However, the nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation, was attenuated in PLCbeta4 knock-out mice. In the dorsal horn of the spinal cord where PLCbeta1 and PLCbeta4 mRNAs are expressed, no difference was found between the wild-type and knock-out mice in the number of Fos-like immunoreactive neurons, which represent neuronal activity in the second phase in the formalin test. Thus, it is unlikely that spinal PLCbeta4 is involved in the formalin-induced inflammatory pain. Next, we found that pretreatment with PLC inhibitors, mGluR1 antagonists, or both, by either intracerebroventricular or intrathalamic injection, attenuated the formalin-induced pain behavior in the second phase in wild-type mice. Furthermore, activation of mGluR1 at the VPL enhanced pain behavior in the second phase in the wild-type mice. In contrast, PLCbeta4 knock-out mice did not show such enhancement, indicating that mGluR1 is connected to PLCbeta4 in the VPL. Finally, in parallel with the behavioral results, we showed in an electrophysiological study that the time course of firing discharges in VPL corresponds well to that of pain behavior in the formalin test in both wild-type and PLCbeta4 knock-out mice. These findings indicate that the thalamic mGluR1-PLCbeta4 cascade is indispensable for the formalin-induced inflammatory pain by regulating the response of VPL neurons.

Endomorphin-2, deltorphin II and their analogs suppress formalin-induced nociception and c-Fos expression in the rat spinal cord

In this study, we evaluated the effects of intrathecally administered agonists of μ- and δ-opioid receptor and their analogs on the pain-induced behavior and expression of c-Fos immunoreactivity in the spinal cord, elicited by intraplantar injection of 12% formalin to the hindpaw of the rat. Previous report from our laboratory and other author's study indicated that intrathecal administration of μ agonists morphine and endomorphin-2 and δ-opioid agonist deltorphin II produced a dose-dependent antinociceptive effects in acute and inflammatory pain. In this study, intrathecal injection of morphine (10 μg), endomorphin-2 (5 μg) and its analog Dmt-endomorphin-2 (10 μg) significantly decreased the formalin-induced pain behavior, and lowered a number of c-Fos positive neurons in the laminae I, II and III of the spinal cord by about 40%, 30% and 40%, respectively. Significant reduction of formalin-induced behavioral responses was also observed after i.th. administration of deltorphin II (15 μg) and its analog ile-deltorphin II (15 μg). Agonists of δ-opioid receptor significantly reduced a number of c-Fos positive neurons by about 28% and 40%, respectively. Analog of endomorphin-2 and analog of deltorphin II suppressed more potently expression of c-Fos in the dorsal horn of the spinal cord than the parent peptides. Our study indicates that new analogs of μ- and δ-opioid receptor exhibit strong antinociceptive potency similar or even higher than the parent peptides, and that their effect is positively correlated with the inhibition of c-Fos expression.

Acupoint stimulation using bee venom attenuates formalin-induced pain behavior and spinal cord fos expression in rats.

In two previous reports, we have demonstrated that injection of bee venom (BV) into an acupoint produces a significant antinociceptive and anti-inflammatory effect in both a mouse model of visceral nociception and a rat model of chronic arthritis. The present study was designed to evaluate the potential antinociceptive effect of BV pretreatment on formalin-induced pain behavior and it associated spinal cord Fos expression in rats. Adult Sprague-Dawley rats were injected with BV directly into the Zusanli (ST36) acupoint or into an arbitrary non-acupoint located on the back. BV pretreatment into the Zusanli acupoint significantly decreased paw-licking time in the late phase of the formalin test. In contrast, BV injected into a non-acupoint in the back region did not suppress the paw-licking time. In addition, BV pretreatment into the Zusanli acupoint markedly inhibited spinal cord Fos expression induced by formalin injection. These findings indicate that BV pretreatment into the Zusanli acupoint has an antinociceptive effect on formalin-induced pain behavior.

Characterization of nociceptin/orphanin FQ-induced pain responses by the novel receptor antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride.

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.

Systemic, but not intrathecal, ketamine produces preemptive analgesia in the rat formalin model.

We investigated the antinociceptive effects of pre- or posttreatment of intrathecal or intravenous ketamine on formalin-induced pain behaviors. Rats were divided into 4 groups of 7 rats each and 2 control groups (saline). Rats received ketamine 1 mg/kg intrathecally (i.t.) through a catheter either 15 min before or 5 min after formalin. In the other groups, they received ketamine 1 mg/kg intravenously (i.v.) through a catheter either 1 min before or 5 min after the formalin. Pain related behavior was quantified by counting the incidence of flinching of the injected paw for 60 min. Formalin induced a biphasic fliching (phase 1, 0-5 min; phase 2, 10-60 min after formalin injection) of injected paw. The inter-group (control, pre, and posttreatment groups) comparisons were performed separately for route of administration (i.t. or i.v.) and phase 1 and 2 using one-way ANOVA and Tukey test. Flinches of phase 1 were not different among the three i.t. groups. The total flinches of phase 2 were reduced by posttreatment with i.t. ketamine (P < 0.05); In contrast, i.v. ketamine was effective only when given as a pretreatment. Flinches of phase 1 and 2 were reduced by pretreatment with i.v. ketamine (P < 0.05). Intrathecal ketamine was an analgesic even when administered as a posttreatment, whereas intravenous ketamine produced effective preemption only when given as a pretreatment.

Heme oxygenase inhibitors reduce formalin-induced Fos expression in mouse spinal cord tissue

Recent work from our laboratory and others supports a role for heme oxygenase in nociception and pain of several etiologies including inflammatory, incisional and neuropathic. Since it has been observed that heme oxygenase inhibitors reduce formalin-induced pain behaviors in mice and rats, we attempted to determine if this analgesic effect was reflected in a reduction in formalin-induced spinal cord Fos expression, an index of neuronal activation. To perform these studies, it was necessary to first examine the cytoarchitecture of the mouse lumbar spinal cord so that histological sections from known segmental levels could be chosen, and Fos-positive nuclei could be assigned to established dorsal horn laminae. After documenting the segmental and laminar distribution of Fos-positive nuclei following a 5% formalin injection, we went on to determine that the heme oxygenase inhibitor tin-protoporphyrin or morphine reduced this Fos expression as analyzed using confocal fluorescence microscopy. It was also observed that mice lacking expression of heme oxygenase type 2, an isozyme of heme oxygenase found in high abundance in the spinal cord, had lowered Fos expression after the formalin injection. Additional confocal microscopy studies demonstrated widespread expression of heme oxygenase type 2 in spinal cord neuron cell bodies. Double-labeling experiments showed that a high percentage of Fos-positive nuclei identified after administration of formalin were located within heme oxygenase type 2-positive cell profiles. Our studies support the hypothesis that heme oxygenase type 2 plays a role in formalin-induced nociception. Furthermore, from these results we suggest that the heme oxygenase type 2 located in spinal cord dorsal horn neurons participates in this nociceptive pathway.

Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors.

ATP activates damage-sensing neurons (nociceptors) and can evoke a sensation of pain. The ATP receptor P2X3 is selectively expressed by nociceptors and is one of seven ATP-gated, cation-selective ion channels. Here we demonstrate that ablation of the P2X3 gene results in the loss of rapidly desensitizing ATP-gated cation currents in dorsal root ganglion neurons, and that the responses of nodose ganglion neurons to ATP show altered kinetics and pharmacology resulting from the loss of expression of P2X(2/3) heteromultimers. Null mutants have normal sensorimotor function. Behavioural responses to noxious mechanical and thermal stimuli are also normal, although formalin-induced pain behaviour is reduced. In contrast, deletion of the P2X3 receptor causes enhanced thermal hyperalgesia in chronic inflammation. Notably, although dorsal-horn neuronal responses to mechanical and noxious heat application are normal, P2X3-null mice are unable to code the intensity of non-noxious 'warming' stimuli.

족삼리(足三里) 봉독약침자극(蜂毒藥鍼刺戟)이 척수내(脊髓內) Fos 양성반응(陽性反應) 신경세포(神經細胞)의 활성(活性)에 미치는 영향(影響)

This study was designed to evaluate the analgesic effect of bee venom (BV) Acupuncture into different treatment points, Chok-samni (ST36) and blank loci of the gluteal muscle and back. We investigated neuronal activity in the spinal cord using the Fos immunohistochemical technique according to the pretreatment with different concentrations of BV, thirty minutes before the formalin injection. The results were summarized as follows: 1. The number of Fos-like immunoreactive (Fos-LI) neurons in L2 segment of the saline-formalin treated group was significantly increased in NECK and VENT of the spinal cord as compared with that of the room control group. However, there was no significant change in the number of the Fos-LI neurons in L2 segment of the BV-formalin treated group as compared with that of the room control group. 2. The number of Fos-LI neurons in L3-5 segment of the saline-formalin group was significantly increased in all the regions of 142 the spinal cord as compared with that of the room control group. However, the Fos-LI neurons in L3-5 segment of the BV-formalin treated group was dramatically decreased in all the regions of the spinal cord as compared with that of the saline-formalin group. Therefore, these results indicated that the BV acupuncture suppressed the nociceptive neuronal activities in L3-5 of the spinal cord induced by formalin injection. 3. There was a strong positive correlation between the formalin-induced pain behavior and the number of the Fos-LI neurons in L3-5 segment.

Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.

We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.

Sympathectomy Decreases Formalin-Induced Nociceptive Responses Independent of Changes in Peripheral Blood Flow

The present experiments studied the effect of surgical sympathectomy on mechanical paw withdrawal thresholds and formalin-induced pain behaviors (FIPB) and tested if the effect of sympathectomy on FIPB is dependent on changes in peripheral blood flow. Compared to sham-operated animals, surgical sympathectomy decreased second phase FIPB but did not affect paw withdrawal thresholds to mechanical stimuli. In sympathectomized and sham-operated animals, subcutaneous intraplantar injection of the nonadrenergic vasoconstrictor angiotensin II (20 μl, 1 mM) or the nonadrenergic vasodilator hydralazine (20 μl, 1 mM) prior to formalin injection decreased and increased peripheral blood flow, respectively. In sympathectomized animals, pretreatment with angiotensin II inhibited the increase of peripheral blood flow following formalin injection when compared to animals pretreated with saline or hydralazine. In sham-operated animals, pretreatment with hydralazine or angiotensin II did not alter vasodilation after formalin injection when compared to pretreatment with saline. Pretreatment with vasoactive drugs had no effect on the sympathectomy-induced decrease in FIPB. It is concluded that sympathectomy decreases FIPB by mechanisms that are independent of sympathectomy-induced changes in peripheral blood flow. The formalin test is an easy, reliable model that can be used to study the mechanisms by which the sympathetic nervous system modulates pain processing.

Halothane effect on formalin-induced paw edema and flinching in rat.

The formalin test is a model of injury-produced inflammatory pain. Anesthetics, in clinically relevant concentrations, affect neutrophils and immune suppression. This study was to determine whether halothane reliably inhibits inflammatory reaction and formalin induced pain behavior or does not. Rats were exposed to 100% oxygen (control) or halothane, respectively for 30 min and then 24 hr later five percent formalin test was assessed. The base values of the paw's diameter were obtained earlier, and then formalin induced edema was assessed by measuring diameters of the injected paws at 5 min, 1 hr, 4 hr and 24 hr after the injection. Nociceptive behavior was quantified by counting the number of times with the paw flinched at 5 min intervals for 60 min. The diameters of edema in the halothane group lessened more than those in the oxygen group at 1 and 24 hr in each following of the injection (p<0.05). The rats pre-administered with oxygen or halothane were similar appearances in nociceptive behaviors. It suggests that halothane anesthesia might inhibit slightly the inflammatory reaction with the formalin-induced edema but might not inhibit the formalin-induced pain behavior in the event of pre-administration halothane 24 hr earlier before the formalin test of rat.

Intrathecal bicuculline does not increase formalin-induced inflammation

Intrathecal (i.t.) administration of the γ-aminobutyric acid (GABA) A receptor antagonist bicuculline enhances pain behaviors in the formalin test. This study examined whether bicuculline also increases the peripheral inflammation induced by formalin. Subcutaneous injection of 0.25 to 5.0% formalin in the plantar surface of one hindpaw of the rat produced a concentration-dependent increase in plasma extravasation as measured by the Evans Blue method. Pretreatment with 0.3 μg i.t. bicuculline neither enhanced nor suppressed formalin-induced plasma extravasation. This dose of bicuculline also did not affect plasma extravasation induced by injection of 3% kaolin/3% carrageenan in the knee of the rat. These data indicate that the enhancement of formalin-induced pain behaviors by i.t. bicuculline is not secondary to enhanced peripheral inflammation, but more likely reflects enhancement of nociceptive transmission in the spinal cord.

Kainate GluR5 receptor subtype mediates the nociceptive response to formalin in the rat

In order to study the roles of the AMPA and kainate subtypes of non-NMDA glutamate receptors in the processing of persistent nociceptive information, compounds with varying activities at these receptors were examined for effects on the formalin-induced paw-licking behavior in rats. The selective AMPA antagonist, LY300164 and the mixed AMPA /kainate antagonist, NBQX, were compared for their effects on formalin-induced pain behavior. NBQX (3, 10, 20 mg/kg, i.p.), caused antinociception as well as ataxia whereas the selective AMPA antagonist, LY300164 (3,5,10 mg/kg, i.p.), did not cause antinociception at doses that did not produce ataxia. In view of the well documented distribution of kainate receptors on C fibres and of the kainate-preferring iGluR5 subtype on dorsal root ganglia (DRG), we tested a series of three decahydroisoquinolines with different profiles of activity between iGluR5 and AMPA receptors and all without activity on iGluR6, iGluR7 or KA2 subtypes. LY293558 (0.1, 1, 3, 5 mg/kg, i.p.), which had low micromolar affinity for both iGluR5 and 2 caused, like NBQX, both antinociceptive and ataxic effects. However, the selective iGluR5 antagonist LY382884 (5, 10, 30, 100 mg/kg, i.p.), exhibited antinociceptive actions without ataxia while the iGluR2 preferring antagonist LY302679 (5 mg/kg, i.p), caused ataxia but did not produce antinociceptive effects at that dose. These actions were stereoselective since the enantiomeric compounds, LY293559 and LY302680, were ineffective in these tests. The data strongly suggest an involvement of iGluR5 in the processing of nociceptive information.

Orphanin FQ potentiates formalin-induced pain behavior and antagonizes morphine analgesia in rats

The present study was designed to observe the effect of orphanin FQ (OFQ, also known as `nociceptin'), a newly-discovered neuropeptide, on pain behavior and morphine analgesia evaluated by formalin test in rats. It was found that intracerebroventricular (i.c.v.) injection of 0.1 μg OFQ had no effect on formalin-induced pain behavior; but 1, 5, 10 or 20 μg OFQ produced prolonged lifting, licking, biting or shaking of the affected paw with higher pain scoring in dose dependent manner. Repeated i.c.v. injection of antisense olignucleotide (ASO) complementary to OFQ receptor but not mismatch olignucleotide (MSO) resulted in the decrease of pain behavior; in such circumstances, OFQ showed no enhancing effect on formalin nociception. OFQ (0.1 or 1 μg, i.c.v.) significantly attenuated morphine analgesia and ASO could validly antagonize the effect of it. Pretreatment with MSO had no such effect. The present results suggest that OFQ enhances the pain behavior of rat and antagonizes morphine analgesia in formalin test.

Neonatal capsaicin treatment abolishes formalin-induced spinal PGE2 release.

We investigated the effect of neonatal capsaicin treatment on formalin-evoked pain behavior and spinal levels of nociceptive neuromodulators using in vivo intrathecal microdialysis in conscious adult rats and age-matched controls. Capsaicin-treated rats displayed thermal hypoalgesia and a significant decrease in tissue content of calcitonin gene-related peptide. Paw swelling, flinching and release of spinal prostaglandin E2 induced by injection of formalin into the hindpaw were also reduced in capsaicin-treated rats compared with controls, whereas glutamate, aspartate and taurine release was unaffected. These data suggest that formalin-induced inflammation, pain behavior and spinal prostaglandin E2 release are mediated by mechanisms sensitive to neonatal capsaicin while the formalin-evoked release of amino acids in the spinal cord is not.

The peripheral antinociceptive effect of morphine in a rat model of facial pain.

The present study compared the peripheral and systemic antinociceptive effect of morphine on formalin-induced facial pain behavior in the rat. Formalin (5%, 50 microliters) was injected subcutaneously into the vibrissal pad of adult rats (250-300 g). Morphine sulfate at doses of 100-1000 micrograms was subcutaneously injected locally (same area) or systemically (in the neck), 30 min before, or simultaneously with, formalin. The typical biphasic face grooming response, consisting of an early phasic phase (0-6 min) and a delayed tonic phase (12-42 min), displayed by control animals, was suppressed by both local and systemic administration of morphine; this effect was dose dependent. However, the suppression of the early phase with local morphine administration 30 min before formalin could be significantly greater (49-52%) than with systemic administration, depending on the dose used. Administration of local morphine simultaneously with formalin produced up to 34% reduction in the early and an additional 32% reduction of the late phases of face grooming, compared to systemic injections. Local injection of naloxone (10 micrograms) almost completely reversed the antinociceptive effect of 1000 micrograms of morphine (early phase 85 +/- 7%, late phase 100 +/- 26% reduction), whereas the same dose of naloxone applied systemically (i.p.) produced only partial reversal (early phase 29 +/- 16%, late phase 36 +/- 1% reduction). This study further indicates that locally administered morphine can exert an analgesic effect superior to systemic administration in the case of inflammatory and non-inflammatory pain through a peripheral site of action. These results support the clinical use of peripheral opioid administration in the treatment of human painful conditions.

Dissociable effects of lidocaine injection into medial versus lateral thalamus in tail-flick and formalin pain tests

Lidocaine was injected into the centromedial (CM) or ventroposterolateral (VPL) thalamic nuclei of alert, unrestrained rats prior to investigation in the formalin and tail-flick tests. Regional anesthesia of CM resulted in a reduction of formalin-induced pain behaviors, while injection into VPL had no significant effect. In the tail-flick test, however, lidocaine injection into VPL caused a significant decrease in withdrawal latencies, indicating increased sensitivity to noxious stimulation. Lidocaine injection into CM was ineffective in the tail-flick test. These results provide evidence of the relatively greater importance of the ‘non-specific’ thalamic nuclei in the expression of tonic pain, and of the VPL in the mediation of withdrawal reflexes to phasic pain.