Induction of long-term potentiation of single wide dynamic range neurones in the dorsal horn is inhibited by descending pathways

Previous studies have shown that long-term potentiation (LTP) in the dorsal horn may be induced by noxious stimuli. In this study it is investigated whether induction of LTP in the dorsal horn may be affected by the descending pathways. Extracellular recordings of wide dynamic range (WDR) neurones in the lumbar dorsal horn in intact urethane-anaesthetized Sprague--Dawley rats were performed, and the electrically evoked neuronal responses in these neurones were defined as A-fibre and C-fibre responses according to latencies. Using a short-term cold block of the thoracic spinal cord, which produced a completely reversible increase of the A-fibre and C-fibre responses, the influence of the descending inhibitory system on the induction of LTP by electrical high-frequency conditioning applied to the sciatic nerve was examined. As previously shown the A-fibre responses were almost unchanged following the conditioning. In contrast, the C-fibre responses following the same conditioning were strongly increased. Thus, a clear LTP of the nociceptive transmission in the dorsal horn was observed following electrical high-frequency conditioning. Interestingly, we found that the LTP was more powerful when the effects of the descending pathways were temporarily eliminated during conditioning. It is concluded that induction of LTP by electrical high-frequency conditioning stimulation, which may be part of the wider term central sensitization, is inhibited by descending pathways.     

Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain

Cancer-induced bone pain is a major clinical problem. A rat model based on intra-tibial injection of MRMT-1 mammary tumour cells was used to mimic progressive cancer-induced bone pain. At the time of stable behavioural changes (decreased thresholds to mechanical and cold stimuli) and bone destruction, in vivo electrophysiology was used to characterize natural (mechanical, thermal, and cold) and electrical-evoked responses of superficial and deep dorsal horn neurones in halothane-anaesthetized rats. Receptive field size was significantly enlarged for superficial neurones in the MRMT-1 animals. Superficial cells were characterised as either nociceptive specific (NS) or wide dynamic range (WDR). The ratio of WDR to NS cells was substantially different between sham operated (growth media alone) (26:74%) and MRMT-1 injected rats (47:53%). NS cells showed no significant difference in their neuronal responses in MRMT-1-injected compared to sham rats. However, superficial WDR neurones in MRMT-1-injected rats had significantly increased responses to mechanical, thermal and electrical (A beta-, C fibre-, and post-discharge evoked response) stimuli. Deep WDR neurones showed less pronounced changes to the superficial dorsal horn, however, the response to thermal and electrical stimuli, but not mechanical, were significantly increased in the MRMT-1-injected rats. In conclusion, the spinal cord is significantly hyperexcitable with previously superficial NS cells becoming responsive to wide-dynamic range stimuli possibly driving this plasticity via ascending and descending facilitatory pathways. The alterations in superficial dorsal horn neurones have not been reported in neuropathy or inflammation adding to the evidence for cancer-induced bone pain reflecting a unique pain state.     

Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy

The mechanisms underlying the relief of neuropathic pain of peripheral origin by spinal cord stimulation (SCS) are poorly understood. The present study was designed to investigate the effects of SCS on evoked and spontaneous discharges in dorsal horn neurons in intact and in nerve-injured rats subjected to partial sciatic nerve ligation according to Seltzer et al. (1990). Tactile sensitivity in the hind paw was assessed in behavioral tests using von Frey filaments. The presence of 'allodynia' was defined as a withdrawal response to a filament of 10 g or less. Under halothane/oxygen anesthesia the effects of SCS (50 Hz, 0.2 ms, 80-620 microA, 5 min.) on mechanically evoked (brush and innocuous press on the hind paw) responses and spontaneous discharges were investigated in wide-dynamic range (WDR) neurons in three groups of animals: (1) rats that displayed 'allodynia' after nerve ligation (2) rats without signs of 'allodynia' after surgery and (3) control, intact rats. A significantly increased frequency of spontaneous discharge and of responsiveness to brush and press was found in the group of allodynic, as compared with non-allodynic and control rats. The majority (63%) of the investigated neurons in these animals displayed afterdischarge in response to press stimulation. SCS induced a significant depression of both the principal response and the afterdischarge in allodynic rats: the discharge during brush stimulation was reduced to 86 +/- 8.2% and during press to 77.4 +/- 4.5% as compared with the prestimulation value. These depressive effects on evoked responses in allodynic rats outlasted SCS by 10.5 +/- 1.7 min during which time the responses gradually recovered. The frequency of spontaneous discharge was markedly decreased in approximately one third of the neurons, whereas in another third it was increased. In non-allodynic and control rats, SCS had no significant depressive effects on the evoked responses and spontaneous discharge. The results suggest that SCS may provide a suppressive action on dorsal horn neuronal hyperexcitability associated with signs of peripheral neuropathy. The suppressive effect of SCS on tactile allodynia, as previously observed in behavioral experiments, presumably corresponds to a normalization of the excitability of WDR cells in response to innocuous stimuli.     

Mu-opioid and noradrenergic α(2)-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats

Multiple pathological mechanisms at multiple sensory sites may underlie the pain that follows nerve injury. This provides a basis for recommending more than one agent, either sequentially or in combination, for its treatment. According to this premise, new drugs that combine different mechanisms of analgesic action in a single molecule are gaining momentum, such as tapentadol which stimulates mu-opioid receptors (MOR) and acts as a noradrenaline reuptake inhibitor (NRI) in the CNS. Tapentadol is currently indicated for treating moderate to severe acute and severe chronic pain, and here we demonstrate its efficacy in an animal model of ongoing neuropathic pain. In particular, we performed a series of in vivo electrophysiological tests in spinal nerve ligated and sham-operated rats to show that systemic tapentadol (1 and 5 mg/kg) dose-dependently reduced evoked responses of spinal dorsal horn neurones to a range of peripheral stimuli, including brush, punctate mechanical and thermal stimuli. Furthermore, we showed that spinal application of the selective α₂-adrenoceptor antagonist atipamezole, or alternatively the mu-opioid receptor antagonist naloxone, produced near complete reversal of tapentadol’s inhibitory effects, which suggests not only that the spinal cord is the key site of tapentadol’s actions, but also that no pharmacology other than MOR-NRI is involved in its analgesia. Moreover, according to the extent that the antagonists reversed tapentadol’s inhibitions in sham and SNL rats, we suggest that there may be a shift from predominant opioid inhibitory mechanisms in control animals, to predominant noradrenergic inhibition in neuropathic animals.     

The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain

The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of spinal versus systemic administration of morphine on the natural and electrically evoked responses of spinal neurones of rats with a selective spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In spinal nerve ligated rats, morphine (0.1-5 microg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1-6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.     

Pathophysiologie des Rückenschmerzes und seine Chronifizierung

The present article concentrates on mechanisms that lead to the excitation of nociceptors in soft tissues and nociceptive neurones in the spinal dorsal horn. These mechanisms may contribute to the so-called unspecific low back pain. Properties of nociceptors in soft tissues: A nociceptive ending in soft tissue contains a multitude of receptor molecules in its membrane. The molecular receptors include binding sites for algesic substances that are released during painful stimulation or pathologic alterations of the tissue: bradykinin (BK), serotonin (5-HT), prostaglandin E2 (PG E2), adenosine triphosphate (ATP) and protons (H(+)). The excitation and sensitisation of nociceptors by these substances can be explained by the binding of the substances to the receptor molecules in the membrane of the receptive ending and ensuing opening of ion channels or activation of metabolic cascades. Purinergic receptor molecules in the membrane of nociceptors are activated by ATP. These receptors may be of particular importance for deep somatic pain, because ATP is present in large amounts in muscle tissue and is released during muscle damage. ATP-sensitive nociceptors appear to be distinct from nociceptors that can be excited by protons. The conduction of nociceptive information from muscle to the spinal cord is partly carried by unmyelinated fibres that possess tetrodotoxin-resistant (TTX-r) Na(+)-channels. Therefore, a drug that specifically blocks TTX-r Na(+)-channels would be a new attractive tool in the treatment of patients with deep somatic pain. Chronic muscle lesions such as a myositis have been shown to be associated with a higher innervation density of the tissue with free nerve endings that contain the neuropeptide substance P (SP). Many of these endings are likely to be nociceptors. Since a painful stimulus that acts on a muscle with increased nociceptor density will excite more nociceptors and elicit more pain, the increase in nociceptor density constitutes a peripheral mechanism for hyperalgesia. In muscle free nerve endings - many of which are nociceptive - the neuropeptides SP, calcitonin gene-related peptide (CGRP) and somatostatin have been shown to be present. These substances are released from the receptive endings in muscle when they are stimulated. SP and CGRP have a strong effect on blood vessels and induce local vasodilatation and oedema. The local oedema in the vicinity of the nociceptor is associated with the release of BK from plasma proteins, which increases the excitability of the nerve ending (see below). Thus, a local vicious cycle forms that may contribute to the formation of trigger points. Sensitisation of nociceptors and peripheral hyperalgesia: Nociceptors are easily sensitised, i.e. following a conditioning stimulus they are more sensitive to the unconditioned stimulus. In animals and humans, the responses to injections of BK can be increased by 5-HT or PG E2. The responses of muscle nociceptors to mechanical stimuli are likewise enhanced after administration of BK. During overuse, ischemia or inflammation of soft tissues, the tissue concentrations of BK, PG E2, and 5-HT are elevated and sensitise muscle nociceptors. A sensitised nociceptor is excited and elicits pain when innocuous mechanical stimuli act on the muscle, e.g. during contractions or stretch. Therefore, in chronically altered soft tissues, weak everyday stimuli are likely to cause pain. Mechanisms at the spinal level: In experiments on rats in which a myositis of the gastrocnemius-soleus (GS) muscle was induced experimentally, the effects of a peripheral painful lesion on the discharge behaviour of sensory dorsal horn neurones were studied. One of the main effects of the myositis was an expansion of the input (target) region of the muscle nerve, i.e. the population of dorsal horn neurones responding to an electrical standard stimulus applied to the GS muscle nerve grew larger. One reason for the myositis-induced expansion of the input region is hyperexcitability of the neurones caused by the release of SP and glutamate from the spinal terminals of muscle afferents with ensuing activation of NMDA channels in dorsal horn neurones (central sensitisation). The central sensitisation is of clinical importance because it can explain the hyperalgesia and spread of pain in patients. In contrast to excitability, the resting activity of dorsal horn neurones - which is likely to induce spontaneous pain in patients - does not appear to depend on the release of SP and glutamate but on the concentration of nitric oxide (NO) in the spinal cord. A pharmacological block of the NO synthesis led to a significant increase in background activity without affecting the excitability of the dorsal horn neurones. Such an increase in background activity was observed exclusively in nociceptive neurones, i.e. a local lack of NO in the spinal cord induces spontaneous pain. According to data from animal experiments, a decrease in the spinal NO concentration occurs as a sequel of a chronic muscle lesion; therefore, a lack of NO is a probable factor for the induction of chronic spontaneous pain. Normally, lesion-induced pain subsides and does not develop into chronic pain. The mechanisms governing the return to normal neuronal behaviour after a peripheral lesion are not well studied. Probably, the activation of inhibitory mechanisms, e.g. increased spinal synthesis of GABA or elevated activity of the descending antinociceptive system contribute to the restoration of normal function. The final step in the transition from acute to chronic pain are structural changes that perpetuate the functional changes. In the rat myositis model, an increase in the number of synapses on the surface of NO-snythesizing cells was present 8 h following induction of the myositis. These data show that structural changes appear quite early in the development of a painful disorder. A novel hypothesis for the development of chronic pain states that a strong nociceptive input to the spinal cord leads to cell death predominantly in inhibitory interneurones. Most of these interneurones are assumed to be tonically active; when their number decreases, the nociceptive neurones are chronically disinhibited and elicit continuous pain also in the absence of a noxious stimulus.     

Are there long-term changes in the basal or evoked Fos expression in the dorsal horn of the spinal cord of the mononeuropathic rat?

The long-term changes in Fos like-immunoreactivity (Fos-LI) in the dorsal horn of the spinal cord following various peripheral nerve lesions remain controversial. This study considers such an approach with chronic constriction injury rats (CCI: loose ligations of the sciatic nerve), at 2 weeks after the surgery, when changes in spontaneous and evoked behaviour were clearly described. All rats used for Fos studies displayed allodynia to mechanical stimulation (decrease of 32% of the vocalization threshold to paw pressure). In CCI rats, which displayed 'spontaneous pain-related behaviour', the number of Fos-LI neurones, in the absence of any intentional stimulation, was very low and comparable with that observed in normal and sham-operated rats (<10 neurones/40 microm section). Thus, in this model, the expression of Fos protein is not a reliable index of spontaneous pain. Surprisingly, despite the fact that in this model numerous anatomical studies described a dramatic loss of large and unmyelinated primary afferent fibers, we were unable to detect changes in the number and distribution of Fos-LI evoked by various modalities of peripheral noxious stimulation (noxious thermal stimuli, noxious mechanical stimuli and carrageenin induced inflammation). For example, the stimulus-response curves for the number of Fos-LI neurones evoked by a series of heat stimuli (40, 45, 48, 52, 55 degrees C) were almost superimposable for CCI, sham-operated and normal rats. In contrast, stroking of the nerve-injured paw induced a significant expression of Fos-LI in the superficial laminae (I-II) of the dorsal horn of CCI rats (19.5 +/- 3/sections, P = 0.027) which was greater than that observed in sham-operated (6.5 +/- 3/sections) or in normal rats (3.5 +/- 2/section). These modifications may reflect mechanical allodynia observed in behavioural studies and could be related to A beta fibers, which are known to be severely affected after the constriction of the nerve. These results suggest that this approach could be useful to study, at the cellular level, in freely moving rats, some pharmacological aspects of neuropathic pain.     

Classical Conditioning Differences Associated With Chronic Pain: A Systematic Review

Prominent clinical models of chronic pain propose a fundamental role of classical conditioning in the development of pain-related disability. If classical conditioning is key to this process, then people with chronic pain may show a different response to pain-related conditioned stimuli than healthy control subjects. We set out to determine whether this is the case by undertaking a comprehensive and systematic review of the literature. To identify studies comparing classical conditioning between people with chronic pain and healthy control subjects, the databases MEDLINE, PsychINFO, PsychARTICLES, Scopus, and CINAHL were searched using key words and medical subject headings consistent with ‘classical conditioning’ and ‘pain.’ Articles were included when: 1) pain-free control and chronic pain groups were included, and 2) a differential classical conditioning design was used. The systematic search revealed 7 studies investigating differences in classical conditioning between people with chronic pain and healthy control participants. The included studies involved a total of 129 people with chronic pain (fibromyalgia syndrome, spinal pain, hand pain, irritable bowel syndrome), and 104 healthy control participants. Outcomes included indices of pain-related conditioning such as unconditioned stimulus (US) expectancy and contingency awareness, self-report and physiological measures of pain-related fear, evaluative judgements of conditioned stimulus pleasantness, and muscular and cortical responses. Because of variability in outcomes, meta-analyses included a maximum of 4 studies. People with chronic pain tended to show reduced differential learning and flatter generalization gradients with respect to US expectancy and fear-potentiated eyeblink startle responses. Some studies showed a propensity for greater muscular responses and perceptions of unpleasantness in response to pain-associated cues, relative to control cues.

Behavioural effects of LTP-inducing sciatic nerve stimulation in the rat

A short-lasting tetanic sciatic nerve stimulation that previously has been shown to be nociceptive only during the stimulation, induces long-term potentiation (LTP) of nociceptive evoked responses in wide dynamic range neurons in the dorsal horn of rats. The LTP may contribute to the process of central sensitization. We have shown that the tetanic conditioning stimulation with muscular contractions induces LTP of both Aβ- and C-fibre evoked responses. However, the same stimulation during muscular paralysis induces LTP only of C-fibre evoked responses. In the present study, we investigated the effects of this conditioning stimulation with or without muscular paralysis in behavioural tests in rats. Conditioning stimulation with muscular contractions caused a significant reduction of weight borne on the stimulated side, suggesting muscular soreness and peripheral sensitization. Conditioning stimulation during neuromuscular paralysis, which only has given LTP of C-fibre evoked responses in intact animals, caused no change in the weight borne on the stimulated side, suggesting less or even absence of allodynia. However, in these animals the response temperature in the hot plate test was increased both on the stimulated and on the contralateral side compared to sham-operated rats. In view of our recent results indicating that a descending inhibition reduces the expression of LTP in dorsal horn cells, and the suggestion by others that long-term descending inhibition may override a segmental facilitation, it is suggested that an increased long-lasting endogenous nociceptive inhibition is induced after LTP-inducing stimulation. This is an interesting parallel to stimulation-induced analgesia in humans. C 1999 European Federation of Chapters of the International Association for the Study of Pain     

Dorsal horn NMDA receptor function is changed after peripheral inflammation

The N-methyl-D-aspartic acid (NMDA) receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP5) caused a stronger inhibition of wind-up in single wide dynamic range (WDR) neurons after carrageenan inflammation compared with control neurons without inflammation in the receptive field. This indicates that even a short period (2.5 h) of inflammation induces changes in the function of NMDA receptors. The drug effect was also studied in separate control experiments with few wind-up inducing stimulus trains and little nociceptive input prior to baseline recordings. In these control experiments all evoked responses were reduced by the drug, but the wind-up was significantly increased. A wind-up increase after NMDA receptor antagonism has been reported in two previous studies. Thus, other mechanisms than NMDA receptor stimulation may be more important for the wind-up in not sensitized dorsal horn neurons. As for long-term potentiation, it seems that NMDA receptor antagonists have an increased effect after sensitization. Thus, sensitized and not sensitized dorsal horn neurons may respond differently to an NMDA receptor active drug. In rats nerve stimulation and halothane anaesthesia induced larger evoked responses to afferent stimulation than cutaneous stimulation and urethane anaesthesia, the AP5 effect was however similar.     

A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats

We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Na(v)1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10-30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30-100 nmol/1 mul) or into the hindpaw receptive field (300 nmol/50 mul) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50-150 nmol/0.5 mul) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Na(v)1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Na(v)1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.     

Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats

The goal of the present study was to examine whether loose ligation of the sciatic nerve was associated with long-term changes in neuronal excitability in the spinal dorsal horn in urethane-anesthetized rats. The sciatic nerve was stimulated with 0. 1 ms long pulses at 1 stimulus/5 min, and the evoked dorsal horn field potentials remained stable in the absence of tetanic stimulation. In one set of control and ligated animals, high-frequency tetanic stimulation was applied to the nerve at 50 Hz (one 400 ms train of twenty 0.1 ms pulses), and the field potentials were recorded again (1 stimulus/5 min) for up to 4 h post-tetanus. In control animals, this protocol produced significant increases in field potential amplitudes at 15, 30 and 60 min post-tetanus. Interestingly, after this time the evoked field potentials began to decrease, and attained less than 50% of their pre-tetanic values at 240 min post-tetanus. In contrast, in ligated rats the pattern of post-tetanic potentiation was significantly different as the increases in amplitude persisted, and at 240 min post-tetanus the field potentials were almost twice their baseline values.In another set of control and ligated animals, low-frequency tetanic stimulation was applied at 5 Hz (one 400 ms train of two 0.1 ms pulses). Again a differential pattern of post-tetanic responses between control and ligated rats was seen. In control animals, a significant decrease in amplitude was evident within 30 min, and the depression became progressively more pronounced as the field potentials attained about a quarter of their baseline values at 180 min, and remained at these low levels at 240 min post-tetanus. On the other hand, in ligated animals, the depression was not significant, and at 240 min post-tetanus the field potentials were still at about 80% of their baseline values.These data demonstrate that long-term changes in spinal dorsal horn neuronal excitability accompany sciatic ligation to perhaps contribute to the development of neuropathic pain. These changes may result from a lessening of normally strong inhibitory processes in the spinal dorsal horn to generate conditions which favor post-tetanic potentiation over depression of dorsal horn neuronal responses.     

Altered effects of an A1 adenosine receptor agonist on the evoked responses of spinal dorsal horn neurones in a rat model of mononeuropathy

There is clinical evidence that adenosine might be a useful treatment for neuropathic pain states, although little is known regarding its mechanisms. In this study, we use the selective (L5/L6) spinal nerve ligation model to investigate the effects of an adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA), on the evoked responses of dorsal horn neurones after nerve injury in vivo. Two weeks after surgery, the responses of dorsal horn neurones to controlled electrical and natural (mechanical and thermal) stimuli were recorded and the effects of intrathecal CPA were compared between nerve-ligated and sham-operated rats. CPA produced significant inhibitions of the C-fiber—evoked response, postdischarge, wind-up, mechanical, and thermal-evoked responses in both groups, but only minor inhibitions of the Aβ-fiber response. Overall, the drug effects in spinal nerve-ligated rats were greater than those of sham-operated rats. Spinal theophylline reversed these inhibitions. In contrast, CPA produced marked facilitations of the Aδ-fiber—evoked neuronal responses in sham-operated animals, yet this effect was completely absent after nerve injury. These results suggest that nerve injury induces plasticity in the spinal A₁ receptor system, which might form the basis for the therapeutic use of adenosine.     

Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy

A total of 68 neurons were recorded from the ventro-postero-lateral nucleus of thalamus (VPL) in rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (n=20), sham operation (n=24) and naive rats (n=24), and effects of the lesion of dorsal column (DC) pathway [DC lesion or DC+gracile nucleus lesions] on VPL nucleus neuronal activities were studied. In the VPL nucleus contralateral to the CCI (receiving input from the injured nerve), response latencies of low threshold mechanoreceptive (LTM) and wide dynamic range (WDR) neurons to electrical stimulation of the sciatic nerve were significantly longer than that in the contralateral VPL nucleus receiving input from the sham-operated side (P<0.05). In contrast, response latencies of LTM and WDR neurons to DC stimulation were not different between the sham operated and CCI sides (0.05). Background activity of WDR neurons was significantly higher in the VPL nucleus contralateral to the CCI side when compared to neurons in the VPL nucleus contralateral to the sham operated side and in naive animals. Responses of LTM and WDR neurons to innocuous mechanical stimulation of the receptive fields were significantly decreased after DC and DC+gracile nucleus lesions in all animals. However, the responses of WDR neurons to noxious stimuli were selectively reduced only in rats with CCI by DC and DC+gracile nucleus lesions (P<0.05). The decrease in noxious stimulus-evoked responses of WDR neurons in the VPL nucleus contralateral to the CCI side after DC and DC+gracile nucleus lesions was greater than that in the VPL nucleus contralateral to the sham operated side and naive animals. These results indicated that DC and DC+gracile nucleus lesions produced selective and stronger effect on noxious responses of VPL nucleus WDR neurons receiving input from the site of nerve injury. The findings suggest that the gracile nucleus-thalamic pathway conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia.     

A hypothesis on the physiological basis for causalgia and related pains

A hypothesis is presented concerning the neuronal mechanisms which subserve the sympathetically maintained pains such as causalgia and reflex sympathetic dystrophy. The hypothesis rests on two assumptions: that a high rate of firing in spinal wide-dynamic-range (WDR) or multireceptive neurons results in painful sensations; and that nociceptor responses associated with trauma can produce long-term sensitization of WDR neurons. The hypothesis states that chronic sympathetically maintained pains are mediated by activity in low-threshold, myelinated mechanoreceptors, that this afferent activity results from sympathetic efferent actions upon the receptors or upon afferent fibers ending in a neuroma and that these afferent fibers evoke sufficient activity in sensitized spinal WDR neurons to produce a painful sensation. This hypothesis is based on known characteristics of these neuronal populations studied in experimental animals and on the observed sensory disturbances reported in patients successfully treated with sympathetic blocks. This hypothesis does not require nerve injury or dystrophic tissue. It explains both the continuous pain and the allodynia that are common to these syndromes and their abolition by sympathetic block. Specific changes are proposed in the diagnosis and treatment of post-traumatic pains.     

Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin

Various mechanisms at peripheral, spinal and/or supraspinal levels may underlie neuropathic pain. The nervous system's capacity for long-term reorganisation and chronic pain may result from abnormalities in RVM facilitatory On cells. Hence, via brainstem injections of the toxic conjugate dermorphin-saporin, which specifically lesions facilitatory cells expressing the mu-opioid receptor (MOR), we sought to determine the influence of these cells in normal and spinal nerve-ligated (SNL) rats. We combined behavioural, electrophysiological and pharmacological techniques to show that the supraspinal facilitatory drive is essential for neuronal processing of noxious stimuli in normal and neuropathic states, and that descending facilitatory neurones maintain behavioural hypersensitivities to mechanical stimuli during the late stages of nerve injury. Furthermore, we showed that these neurones are essential for the state-dependent inhibitory actions of pregabalin (PGB), a drug used in the treatment of neuropathic pain. During the early stages of nerve injury, or following medullary MOR cell ablation, PGB is ineffective at inhibiting spinal neuronal responses possibly due to quiescent spinal 5HT(3) receptors. This can however be overcome, and PGB's efficacy restored, by pharmacologically mimicking the descending drive at the spinal level with a 5HT(3) receptor agonist. Since RVM facilitatory neurones are integral to a spino-bulbo-spinal loop that reaches brain areas co-ordinating the sensory and affective components of pain, we propose that activity therein may influence painful outcome following nerve injury, and responsiveness to treatment.     

Effects of midazolam in the spinal nerve ligation model of neuropathic pain in rats

Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L(5) and L6 spinal nerves was performed in adult male Sprague-Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15-18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C-fibre threshold. The rats in the spinal nerve ligation group, but not in the sham-operated control group developed mechanical and cold allodynia. Subcutaneous administration of midazolam 0.1-3.0 mg/kg reduced the Adelta-fibre evoked activity in a dose-related manner in all study groups, but the C-fibre evoked activity was significantly reduced only in the spinal nerve ligation group. The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C-fibre evoked firing significantly more in the spinal nerve ligation model than in the non-operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.     

Inhibition of evoked C-fibre responses in the dorsal horn after contralateral intramuscular injection of capsaicin involves activation of descending pathways

In this study extracellular recordings of nociceptive dorsal horn neurones driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. Spikes 0-40, 40-250 and 250-800 ms after stimulus were defined as A- and C-fibre responses and post-discharge, respectively, and the effect of 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was investigated. In most cells tested, regardless of the size or location of their receptive fields, the injection of capsaicin caused a clear inhibition of the electrically evoked C-fibre responses. In animals with intact descending pathways the mean C-fibre response was inhibited to 51% of baseline 15 min after injection of capsaicin. In contrast, when capsaicin was given during cold block of the spinal cord between the brainstem and the site of recording in the dorsal horn, the same response was inhibited to 91% of baseline. A significant interaction between cold block and capsaicin was detected. We conclude that stimulation of capsaicin-sensitive afferents in the deep tissue in the hind limb can inhibit the electrically evoked C-fibre responses in the dorsal horn by activating inhibitory descending projections from higher centres. The model presented here may be an important tool for further investigations of the endogenous descending antinociceptive system.     

The persistence of a long-term negative affective state following the induction of either acute or chronic pain

Clinically, pain is a complex phenomenon consisting of both sensory and affective aberrations that can persist indefinitely. Pre-clinically, several animal paradigms have been established that reliably mimic both the acute and chronic aspects of pain pertinent to the human condition; however, the commonly used behavioral models only assess the sensory component of pain elicited by an evoked nociceptive stimulus. Since the affective-motivational component of pain is an important determinant of the overall pain experience in man, we investigated how this aspect may be modeled long-term in rats using novel objects and a modified conditioned place aversion (CPA) paradigm. Findings demonstrate that animals subjected to either neuropathic injury or inflammatory insult display a significant conditioned place aversion to a pain-paired environment that is paralleled by an increased number of hind paw withdrawals and fewer number of novel object interactions during painful conditioning sessions. Moreover, this aversion is maintained for 1 month in the absence of further conditioning. We also determined that a non-analgesic, non-rewarding dose of morphine administered prior to pain-paired conditioning sessions attenuates the pain-induced aversion and its relative persistence in both pain models. Together, these findings underscore the importance of negative affect accompanying painful conditions and its long-term persistence even when the injury or insult has resolved. Lastly, these results suggest how both sensory and affective aberrations associated with neuropathic- and inflammatory-like conditions and the memory of such known to impact quality of life in man may be addressed pre-clinically in rodents.