Zhiyang Song

Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy

Abstract The mechanisms underlying the pain relieving effect of spinal cord stimulation (SCS) on neuropathic pain remain unclear. We have previously demonstrated that suppression of tactile hypersensitivity produced by SCS may be potentiated by i.t. clonidine in a rat model of mononeuropathy. Since the analgesic effect of this drug is mediated mainly via cholinergic mechanisms, a study exploring the possible involvement of the spinal cholinergic system in SCS was undertaken. The effect of SCS was assessed with von Frey filaments in rats displaying tactile hypersensitivity after partial ligation of the sciatic nerve and both SCS‐responding and non‐responding as well as normal rats were subjected to microdialysis in the dorsal horn. Acetylcholine (ACh) was analyzed with HPLC before, during and after SCS. SCS produced significantly increased release of ACh in the dorsal horn in rats responding to SCS whereas the release was unaffected in the non‐responding animals. Furthermore, the basal release of ACh was significantly lower in nerve lesioned than in normal rats. In another group of rats it was found that the response to SCS was completely eliminated by i.t. atropine and a muscarinic M4 receptor antagonist while a partial attenuation was produced by M1 and M2 antagonists. Blocking of nicotinic receptors did not influence the SCS effect. In conclusion, the attenuating effect of SCS on pain related behavior is associated with the activation of the cholinergic system in the dorsal horn and mediated via muscarinic receptors, particularly M4, while nicotinic receptors appear not to be involved.

Pain relief by spinal cord stimulation involves serotonergic mechanisms: an experimental study in a rat model of mononeuropathy.

ABSTRACT The aim of the present study was to examine the role of the spinal serotonergic system in the pain relieving effect of spinal cord stimulation (SCS) using a rat model of mononeuropathy. Tactile withdrawal thresholds, cold responses and heat withdrawal latencies were assessed before and after SCS. In some rats, SCS produced an attenuation of the hypersensitivity following nerve injury (SCS responding rats). When SCS was applied immediately prior to sacrifice, the 5‐HT content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was increased in SCS responding rats. But there was no change in responding rats without stimulation, or in SCS non‐responding rats with or without stimulation or in controls. Immunohistochemical examination showed a high density of 5‐HT stained terminals in the dorsal horn superficial laminae (I‐II) in SCS responding rats following stimulation. It was also found that i.t. administration of a sub‐effective dose of serotonin in SCS non‐responding rats markedly enhanced the pain relieving effect of SCS on tactile and cold hypersensitivity, while there was no effect on heat hyperalgesia. This enhanced effect on tactile hypersensitivity could be partially blocked by a GABAB receptor antagonist (CGP 35348) but not by a muscarinic M4 receptor antagonist (Muscarinic toxin 3) administered i.t. shortly before the 5‐HT injection. In conclusion, there is evidence that the spinal 5‐HT system plays an important role in the mode of action of SCS involving the activation of descending serotonergic pathways that may inhibit spinal nociceptive processing partially via a GABAergic link.

Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy

&NA; Spinal cord stimulation (SCS) is extensively employed in the management of neuropathic pain, but the underlying mechanisms are only partially understood. Recently, we demonstrated that the pain‐relieving effect of SCS appears to involve the spinal serotonin system, and the present study aimed at identifying the types of the spinal serotonin receptors involved. Experiments were performed on rats with neuropathy produced by partial ligation of the sciatic nerve. Tactile sensitivity was assessed using von Frey filaments, and cold and heat sensitivity with cold spray and radiant heat, respectively. Selective 5‐HT receptor antagonists, methiothepin (5‐HT1,6,7), ketanserin tartrate (5‐HT2A), TICM (5‐HT3), SDZ‐205,557 (5‐HT4), as well as receptor agonists, α‐m‐5‐HT (5‐HT2), m‐CPBG (5‐HT3) in per se ineffective doses, or vehicle, were administrated intrathecally 5 minutes prior to the application of SCS. Ketanserin and SDZ‐205,557 significantly attenuated the suppressive effect of SCS on tactile hypersensitivity, while methiothepin and TICM were ineffective. The suppressive effect on cold hypersensitivity of SCS was counteracted by ketanserin only. None of the 5‐HT receptor antagonists attenuated the suppressive effect on heat hyperalgesia of SCS. Subeffective doses of α‐m‐5‐HT and m‐CPBG enhanced the suppressive effect of SCS on tactile hypersensitivity. The enhancing effect of m‐CPBG was abolished by a γ‐aminobutyric acid (GABA)A or GABAB antagonist intrathecally. These results suggest that the activation of 5‐HT2A, 5‐HT3, and 5‐HT4 receptors plays an important role in SCS‐induced relief of neuropathic pain. The activation of 5‐HT3 receptors appears to operate via spinal GABAergic interneurons. The activation of 5‐HT2A, 5‐HT3, and 5‐HT4 receptors plays an important role in spinal cord stimulation‐induced relief of neuropathic pain.

Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: An experimental study in a rat model of neuropathy

Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50 Hz, 0.2 ms, 2-4V, 5 min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (α-adrenergic), propranolol (β-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems.

Therapy using implanted organic bioelectronics

Implanted organic bioelectronics provide possible alternative to existing pain treatments. Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics.

Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy

Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.

Efficacy of Kilohertz-Frequency and Conventional Spinal Cord Stimulation in Rat Models of Different Pain Conditions

The aim was to compare the effects of high‐frequency spinal cord stimulation (HF‐SCS) at subparesthetic intensity with conventional SCS in rat models of different types of pain. In addition, microrecordings of afferent activity in the dorsal columns during both types of SCS were performed to elucidate their mode of action.

Exploration of supraspinal mechanisms in effects of spinal cord stimulation: role of the locus coeruleus.

The neurobiological mechanisms of spinal cord stimulation (SCS) when applied for neuropathic pain are still incompletely known. Previous research indicates that brainstem circuitry is pivotal for the SCS effect. The present study aims at exploring the possible contribution to the SCS effects of the pain controlling system emanating from the locus coeruleus (LC) in the brain stem. Experiments were performed on the rat-spared nerve injury pain model. After evaluation of the attenuation of mechanical hypersensitivity induced by SCS, the effects of SCS on neuronal activity in the LC and on the noradrenaline (NA) content in the dorsal spinal cord were analyzed. SCS produced a significant increase in the discharge rate of LC neurons only in rats behaviorally responding to SCS as compared to non-responding and control animals. The NA content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was analyzed using enzyme-linked immunosorbent assay in responding, non-responding and intact control rats both immediately following SCS and without SCS. No differences were found between these groups. In awake animals, lidocaine silencing of the ipsilateral LC or blocking of spinal noradrenergic system by intrathecal administration of α1,2 adrenoceptor antagonists failed to influence the antihypersensitivity effect of SCS. The present results indicate that the SCS-induced control of hypersensitivity in an experimental animal model of peripheral neuropathic pain may not be explained by the activation of direct spinal projections of noradrenergic LC neurons, while supraspinal projections of LC neurons still may play a role in the SCS effect.

The rostroventromedial medulla is engaged in the effects of spinal cord stimulation in a rodent model of neuropathic pain.

The neurobiological mechanisms underlying the suppression of neuropathic pain by spinal cord stimulation (SCS) are still incompletely known. The present study aims at exploring whether the descending pain control system in the rostroventromedial medulla (RVM) exerts a role in the attenuation of neuropathic pain by SCS. Experiments were performed in the rat spared nerve injury (SNI) pain model. The effects of SCS on neuronal activity of pronociceptive ON-like, antinociceptive OFF-like, and neutral cells, including 5-HT-like cells, in the RVM were analyzed in SCS responding and SCS non-responding SNI animals as well as in naïve controls. Decreased spontaneous activities in OFF-like cells and increased spontaneous activities in ON-like cells were observed in SNI animals, whereas the spontaneous activities of 5-HT-like and neutral cells were unchanged. SCS produced a prominent increase in the discharge of OFF- and 5-HT-like cells in SCS responding, but not in non-responding SNI animals or controls. Discharge rates of ON-like and neutral cell were not affected by SCS. In awake SNI animals, microinjection of a GABAA receptor agonist, muscimol, into the RVM significantly attenuated the antihypersensitivity effect induced by SCS while a non-selective opioid receptor antagonist, naltrexone, was ineffective. It is concluded that SCS may shift the reciprocal inhibitory and facilitatory pain modulation balance controlled by the RVM in favor of inhibition. This increase in the descending antinociceptive effect operates in concert with segmental spinal mechanisms in producing pain relief.

The interaction between antidepressant drugs and the pain-relieving effect of spinal cord stimulation in a rat model of neuropathy.

BACKGROUND: Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. On the basis of our previous studies on the mode of action of SCS, intrathecal administration of subeffective doses of certain drugs has been shown to enhance the pain-relieving effect in patients with SCS. Antidepressants have a well-established beneficial effect in neuropathic pain. We performed the present study to examine potential synergistic or antagonistic effects on SCS of antidepressants: amitriptyline (tricyclic antidepressant), fluoxetine (selective serotonin reuptake inhibitor), and milnacipran (selective serotonin/noradrenaline reuptake inhibitor). METHODS: In rats, the effect of SCS on mechanical hypersensitivity after peripheral nerve injury was assessed in awake, freely moving animals. Antidepressants were administered intrathecally. RESULTS: When combining SCS with subeffective doses of amitriptyline or milnacipran, the suppressive effect of SCS on the mechanical hypersensitivity was enhanced in comparison with that obtained with SCS alone. There was no detectable effect of fluoxetine. No signs of an antagonistic effect of the drugs on the SCS effect were observed. CONCLUSIONS: These findings suggest a possible clinical application with a combination of SCS and a tricyclic antidepressant or selective serotonin/noradrenaline reuptake inhibitor drug in cases in which SCS per se has proven inefficient.