Sex-related correspondence between mechanical hypersensitivity and the discharge of medullary pain control neurons in neuropathic rats.

Here we studied whether the sex-related difference in mechanical hypersensitivity induced by neuropathy is associated with the discharge rate of medullary pain control neurons. We performed experiments in male and female rats with spared nerve injury (SNI) model of peripheral neuropathy. Mechanical hypersensitivity was assessed behaviorally by monofilaments. Discharge rates of pain-control neurons were determined using in vivo single unit recordings under light anesthesia. Recording targets were two medullary nuclei involved in descending pain control: the rostral ventromedial medulla (RVM) and the medullary dorsal reticular nucleus (DRt). Based on the response to peripheral noxious stimulus, neurons were classified as pronociceptive RVM ON-like or DRt neurons, or antinociceptive RVM OFF-like neurons. Behavioral results indicated that the mechanical hypersensitivity induced by SNI was significantly stronger in females than males. The ongoing discharge rates of pronociceptive RVM ON-like neurons were higher and those of antinociceptive RVM OFF-like neurons lower in SNI females than SNI males. Ongoing discharge rates of pronociceptive DRt neurons were not significantly different between SNI females and males. The results suggest that a sex difference in the discharge rate of pain control neurons in the RVM but not DRt may contribute to the maintenance of stronger neuropathic hypersensitivity in females.

Injection of kaolin/carrageenan in the rat knee joint induces progressive experimental knee osteoarthritis.

ABSTRACT: Osteoarthritis (OA), the most common joint disorder worldwide, is characterized by progressive degeneration of articular and periarticular structures, leading to physical and emotional impairments that greatly affect the quality of life of patients. Unfortunately, no therapy has been able to halt the progression of the disease. Owing to the complexity of OA, most animal models are only able to mimic a specific stage or feature of the human disorder. In this work, we demonstrate the intraarticular injection of kaolin or carrageenan leads to the progressive degeneration of the rat's knee joint, accompanied by mechanical hyperalgesia and allodynia, gait impairments (reduced contact area of the affected limb), and radiological and histopathological findings concomitant with the development of human grade 4 OA. In addition, animals also display emotional impairments 4 weeks after induction, namely, anxious and depressive-like behaviour, important and common comorbidities of human OA patients. Overall, prolonging kaolin or carrageenan-induced monoarthritis mimics several important physical and psychological features of human OA in both male and female rodents and could be further applied in long-term studies of OA-associated chronic pain.

Reduced mechanical hypersensitivity by inhibition of the amygdala in experimental neuropathy: Sexually dimorphic contribution of spinal neurotransmitter receptors.

Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male and female rats with spared nerve injury (SNI) model of neuropathy. SNI induced mechanical hypersensitivity that was stronger in females. Reversible blocking of the CeA with muscimol (GABAA receptor agonist) induced a reduction of mechanical hypersensitivity that did not differ between males and females. Following spinal co-administration of atipamezole (α2-adrenoceptor antagonist), the reduction of mechanical hypersensitivity by CeA muscimol was attenuated more in males than females. In contrast, following spinal co-administration of raclopride (dopamine D2 receptor antagonist) the reduction of hypersensitivity by CeA muscimol was attenuated more in females than males. The reduction of mechanical hypersensitivity by CeA muscimol was equally attenuated in males and females by spinal co-administration of WAY-100635 (5-HT1A receptor antagonist) or bicuculline (GABAA receptor antagonist). The CeA muscimol induced attenuation of ongoing pain-like behavior (conditioned place preference test) that was reversed by spinal co-administration of atipamezole in both sexes. The results support the hypothesis that CeA contributes to mechanical hypersensitivity and ongoing pain-like behavior in SNI males and females. Disinhibition of descending controls acting on spinal α2-adrenoceptors, 5-HT1A, dopamine D2 and GABAA receptors provides a plausible explanation for the reduction of mechanical hypersensitivity by CeA block in SNI. The involvement of spinal dopamine D2 receptors and α2-adrenoceptors in the CeA muscimol-induced reduction of mechanical hypersensitivity is sexually dimorphic, unlike that of spinal α2-adrenoceptors in the reduction of ongoing neuropathic pain.

Thalamus: The 'promoter' of endogenous modulation of pain and potential therapeutic target in pathological pain.

More recently, the thalamic mediodorsal (MD) and ventromedial (VM) nuclei have been revealed to be functioned as 'nociceptive discriminator' in discriminating noxious and innocuous peripheral afferents, and exhibits distinct different descending controls of nociception. Of particularly importance, the function of thalamic nuclei in engaging descending modulation of nociception is 'silent' or inactive during the physiological state as well as in condition exposed to insufficient noxious stimulation. Once initiation by sufficient noxious or innocuous C-afferents associated with temporal and spatial summation, the thalamic MD and VM nuclei exhibit salient, different effects: facilitation and inhibition, on noxious mechanically and heat evoked nociception, respectively. Based on series of experimental evidence, we here summarize a novel hypothesis involving thalamic MD and VM nuclei functioned as 'promoter' in initiating descending facilitation and inhibition of pain with specific spatiotemporal characteristics. We further hypothesize that clinical remedy in targeting thalamic VM nucleus by enhancing its activities in recruiting inhibition alone or decreasing thalamic MD nucleus induced facilitation may provide promising way in effectively control of pathological pain.

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1.

Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1. Pain sensitivity was assessed behaviorally by using mechanical and heat stimuli. Effect on the discharge rate of rostral ventromedial medullary (RVM) pain control neurons was studied in lightly anesthetized animals. Netrin-1, in a dose-related fashion, induced mechanical hypersensitivity that lasted up to three weeks. Netrin-1 had no effect on heat nociception. Mechanical hypersensitivity induced by netrin-1 was attenuated by TRPA1 antagonist Chembridge-5861528 and by the control analgesic compound pregabalin both during the early (first two days) and late (third week) phase of hypersensitivity. TRPC4/C5 antagonist ML-204 had a weak antihypersensitivity effect that was only in the early phase, whereas TRPC4/C5 antagonist HC-070 had no effect on hypersensitivity induced by netrin-1. The discharge rate in pronociceptive ON-like RVM neurons was increased by netrin-1 during the late but not acute phase, whereas netrin-1 had no effect on the discharge rate of antinociceptive RVM OFF-like neurons. The results suggest that spinal TRPA1 receptors and pronociceptive RVM ON-like neurons are involved in the maintenance of submodality-selective pronociceptive actions induced by netrin-1 in the spinal cord.

Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons.

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.

Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat.

BACKGROUND: Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ1 and NMDA receptors, gap junctions and D-amino acid oxidase. METHODS: Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (σ1 receptor antagonist), carbenoxolone (a gap junction decoupler), MK-801 (NMDA receptor antagonist) and AS-057278 (inhibitor of D-amino acid oxidase, DAAO) were used to prevent the DMS-induced hypersensitivity, and pregnenolone sulphate (TRPM3 agonist) to recapitulate hypersensitivity. RESULTS: DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin. CONCLUSIONS: Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the σ1 and NMDA receptors, and DAAO.

Neurophysiological response properties of medullary pain-control neurons following chronic treatment with morphine or oxycodone: modulation by acute ketamine.

Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid, is not yet known. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone.NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-d-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.

Effects of Heating-needle Stimulation in Restoration of Weakened Descending Inhibition of Nociception in a Rat Model of Parkinson's Disease.

Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson's disease (PD) induced by unilateral microinjection of 3.5 µl of 2.5 µg/µl 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P < 0.05). Striatal administration of 5 µg of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P < 0.05). I.m. 43 °C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P < 0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P < 0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 °C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD.

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors.

Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50-200 µl) of complete Freund's adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5-14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30-45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30-45 min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5-4.5 nmol/0.5 µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.

Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury.

BACKGROUND: The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior. METHODS: Rats with a spared nerve injury (SNI) model of neuropathy or sham operation had a chronic cannula for drug microinjections into the CeA or a control injection site. Monofilament test was used to evaluate pain, and light-dark box (LDB) to assess anxiety. RESULTS: Perioperative CeA treatment with TPA (30 µg/day up to the third postoperative day, D3) significantly attenuated the development of pain and anxiety-like behavior. In the late phase (> D14), CeA administration of TPA (3-30 µg) failed to influence pain. Perioperative minocycline (microglia inhibitor; 25 µg), MK-801 (an N-Methyl-D-aspartate receptor antagonist; 0.1 µg), vehicle or TPA in a control injection site failed to attenuate pain development. CONCLUSIONS: Perioperative treatment of the CeA with TPA delayed development of neuropathic pain and comorbid anxiety-like behavior, while TPA treatment failed to influence maintenance of established neuropathic pain. The failures to attenuate pain development with CeA administrations of minocycline or MK-801 do not support the hypothesis that the TPA-induced prophylactic effect was due to inhibition of amygdaloid microglia or N-methyl-D-aspartate receptors. While TPA in the CeA proved to have a prophylactic effect on SNI-induced pain behavior, the underlying mechanism still remains to be studied.

TRPA1 Antagonists for Pain Relief.

Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment.

Dopaminergic and serotonergic mechanisms in the modulation of pain: In vivo studies in human brain.

Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D2/D3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D2/D3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D2/D3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D2/D3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D2/D3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D2/D3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D2/D3 receptors. These findings suggest that dopamine acting on striatal dopamine D2/D3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.

Anxiety- and activity-related effects of paracetamol on healthy and neuropathic rats.

Paracetamol has recently been suggested to affect emotion processing in addition to alleviating pain in humans. We investigated in adult male Hannover-Wistar rats whether acute intraperitoneally administrated paracetamol affects behavior in tests measuring anxiety, mood, motor activity, and memory. Unoperated rats received saline or a low (50 mg/kg) or high (300 mg/kg) dose of paracetamol, while rats with a spared nerve injury (SNI) model of neuropathy and sham-operated rats received saline or the low dose of paracetamol. Rats were tested on open-field (OFT), elevated plus-maze (EPM), light-dark box (LDB), novel-object recognition (NOR), sucrose preference, rotarod, and monofilament tests. In unoperated rats, both the low and high dose of paracetamol reduced line crossings, and grooming time in the OFT, and novel preference in NOR. The high dose of paracetamol increased the time spent in the closed arm in EPM, reduced the number of rearings and leanings in OFT, the time spent in the light box in LDB, and sucrose preference. Paracetamol had no significant effect on the rotarod test measuring motor activity. The low dose of paracetamol suppressed mechanical pain hypersensitivity in SNI rats, without influencing pain behavior in sham-operated rats. Saline- but not paracetamol-treated SNI rats spent more time than sham-operated rats in the closed arm in the EPM test. Together the results suggest that a high dose of paracetamol increases anxiety-like and anhedonic behavior, and impairs recognition memory in unoperated controls, while in neuropathy, a low dose of paracetamol reduces nerve injury-associated anxiety probably by reducing neuropathic pain.

Neural Substrate for Metacognitive Accuracy of Tactile Working Memory.

The human prefrontal cortex (PFC) has been shown to be important for metacognition, the capacity to monitor and control one's own cognitive processes. Here we dissected the neural architecture of somatosensory metacognition using navigated single-pulse transcranial magnetic stimulation (TMS) to modulate tactile working memory (WM) processing. We asked subjects to perform tactile WM tasks and to give a confidence rating for their performance after each trial. We circumvented the challenge of interindividual variability in functional brain anatomy by applying TMS to two PFC areas that, according to tractography, were neurally connected with the primary somatosensory cortex (S1): one area in the superior frontal gyrus (SFG), another in the middle frontal gyrus (MFG). These two PFC locations and a control cortical area were stimulated during both spatial and temporal tactile WM tasks. We found that tractography-guided TMS of the SFG area selectively enhanced metacognitive accuracy of tactile temporal, but not spatial WM. Stimulation of the MFG area that was also neurally connected with the S1 had no such effect on metacognitive accuracy of either the temporal or spatial tactile WM. Our findings provide causal evidence that the PFC contains distinct neuroanatomical substrates for introspective accuracy of tactile WM.

Role of capsaicin- and heat-sensitive afferents in stimulation of acupoint-induced pain and analgesia in humans.

We investigated role of capsaicin-sensitive afferents within and without the areas of Zusanli (ST36)/Shangjuxu (ST37) acupoints along the stomach (ST) meridian in the perception and modulation of pain assessed by visual analog scale of pain and its distribution rated by subjects, pressure pain threshold (PPT), and heat pain threshold (HPT) in humans. Compared with the treatment of non-acupoint area, capsaicin (100µg/50µl) administered into either ST36 or ST37 acupoint caused the strongest pain intensity and the most extensive pain distribution, followed by rapid onset, bilateral, long-lasting secondary mechanical hyperalgesia and slower onset secondary heat hypoalgesia (1day after the capsaicin treatment). Between treatments of different acupoints, capsaicin administrated into the ST36 acupoint exhibited the stronger pain intensity and more widespread pain distribution compared with the treatment of ST37 acupoint. A period of 30- to 45-min, but not 15-min, 43°C heating-needle stimulation applied to the ST36 acupoint significantly enhanced the HPT, and had no effect on PPT. Upon trapezius muscle pain elicited by the i.m. injection of 5.8% saline, pre-emptive treatment of the contralateral ST36 acupoint with 43°C heating-needle stimulation alleviated the ongoing muscle pain, reduced painful area, and reversed the decrease in HPT. It is suggested that (1) pain elicited from the acupoint and non-acupoint areas differs significantly, which are supposed to be dependent on the different distributions and contributions of capsaicin-sensitive afferents. (2) Non-painful heat stimulation is a valid approach in prevention of ongoing muscle pain with associated post-effects of peripheral and central sensitization.

Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat.

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.

The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex.

Metabotropic glutamate receptor 5 (mGluR5) activation in the infralimbic cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals. Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat-evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats. The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.