Entanglement between thermoregulation and nociception in the rat: the case of morphine.

In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "off-" neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index.

The rostral ventromedial medulla control of cutaneous vasomotion of paws and tail in the rat: implication for pain studies.

Thermal neutrality in rodents is achieved by large cyclic variations of the sympathetic drive of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Given the pivotal functional role of rostral ventromedial medulla (RVM) in nociception and rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, we aimed at circumscribing the brainstem regions that are the source of premotor afferents to sympathetic preganglionic neurons that control the vasomotor tone of the tail and hind paws. A thermometric infrared camera recorded indirectly the vasomotor tone of the tail and hind paws. During the control period, the rat was maintained in vasoconstriction by preserving a stable, homogeneous, and constant surrounding temperature, slightly below the core temperature. The functional blockade of the RVM/rMR by the GABAA receptor agonist muscimol (0.5 nmol, 50 nl) elicited an extensive increase of the temperature of the paws and tail, associated with a slight decrease of blood pressure and heart rate. Both the increased heat loss through vasodilatation and the decrease heart-induced heat production elicited a remarkable reduction of the central temperature. The effective zones were circumscribed to the parts of the RVM/rMR facing the facial nucleus. They match very exactly the brain regions often described as specifically devoted to the control of nociception. Our data support and urge on the highest cautiousness regarding the interpretation of results aimed at studying the effects of any pharmacological manipulations of RVM/rMR with the usual tests of pain.

Thermoregulatory vasomotor tone of the rat tail and paws in thermoneutral conditions and its impact on a behavioral model of acute pain.

The tail and paws in rodents are heat exchangers involved in the maintenance of core body temperature (T(core)). They are also the most widely used target organs to study acute or chronic "models" of pain. We describe the fluctuations of vasomotor tone in the tail and paws in conditions of thermal neutrality and the constraints of these physiological processes on the responses to thermal nociceptive stimuli, commonly used as an index of pain. Skin temperatures were recorded with a calibrated thermal camera to monitor changes of vasomotor tone in the tail and paws of awake and anesthetized rats. In thermoneutral conditions, the sympathetic tone fluctuated at a rate of two to seven cycles/h. Increased mean arterial blood pressure (MAP; ∼46 mmHg) was followed by increased heart rate (HR; ∼45 beats/min) within 30 s, vasoconstriction of extremities (3.5-7°C range) within 3-5 min, and increased T(core) (∼0.7°C) within 6 min. Decreased MAP was followed by opposite events. There was a high correlation between HR and T(core) recorded 5-6 min later. The reaction time of the animal's response to a radiant thermal stimulus-heat ramp (6°C/s, 20 mm(2) spot) generated by a CO2 laser-directed to the tail depends on these variations. Consequently, the fluctuations in tail and paw temperature thus represent a serious confound for thermal nociceptive tests, particularly when they are conducted at thermal neutrality.

"On-" and "off-" cells in the rostral ventromedial medulla of rats held in thermoneutral conditions: are they involved in thermoregulation?

In thermal neutral condition, rats display cyclic variations of the vasomotion of the tail and paws, synchronized with fluctuations of blood pressure, heart rate, and core body temperature. "On-" and "off-" cells located in the rostral ventromedial medulla, a cerebral structure implicated in somatic sympathetic drive, 1) exhibit similar spontaneous cyclic activities in antiphase and 2) are activated and inhibited by thermal nociceptive stimuli, respectively. We aimed at evaluating the implication of such neurons in autonomic regulation by establishing correlations between their firing and blood pressure, heart rate, and skin and core body temperature variations. When, during a cycle, a relative high core body temperature was reached, the on-cells were activated and within half a minute, the off-cells and blood pressure were depressed, followed by heart rate depression within a further minute; vasodilatation of the tail followed invariably within ∼3 min, often completed with vasodilatation of hind paws. The outcome was an increased heat loss that lessened the core body temperature. When the decrease of core body temperature achieved a few tenths of degrees, sympathetic activation switches off and converse variations occurred, providing cycles of three to seven periods/h. On- and off-cell activities were correlated with inhibition and activation of the sympathetic system, respectively. The temporal sequence of events was as follows: core body temperature → on-cell → off-cell ∼ blood pressure → heart rate → skin temperature → core body temperature. The function of on- and off-cells in nociception should be reexamined, taking into account their correlation with autonomic regulations.

Psychophysics of a nociceptive test in the mouse: ambient temperature as a key factor for variation.

BACKGROUND: The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and latency of the central decision-making process. METHODOLOGY/PRINCIPAL FINDINGS: Basically, the procedures involved heating of the tail with a CO(2) laser, recording of tail temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making. CONCLUSIONS/SIGNIFICANCE: We have validated a psychophysical approach to nociceptive reactions for the mouse, which has already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using as "pain index" the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing of mice.

Dose-dependent opposite effects of gabapentin on the depressive action of morphine on a C-fibre reflex in the rat.

Gabapentin is a structural analogue of gamma-amino-butyric acid with anticonvulsant activity. Recently, indications for its use were extended to the management of acute pain in the postoperative period. The effects of pre-administration of gabapentin on the depressive action of intravenous morphine were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats with either an intact neuraxis or a brainstem previously transected at the level of the obex. As previously reported, 6 mg/kg intravenous morphine both increased the threshold and decreased the slope of the stimulus-response recruitment curve. The C-fibre reflex was not modified following intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01-7.5 mg/kg) not only antagonized the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10-50 mg/kg), gabapentin pre-treatment potentiated the depressive effect of morphine. In obex-transected rats, the facilitation of the C-fibre reflex, seen following 1 mg/kg gabapentin and 6 mg/kg morphine, disappeared and was replaced by a strong reinforcement of the depressive effect of morphine. It is concluded that a strong synergy between the effects of gabapentin and morphine can be seen at the spinal level. However, radically opposite effects with supraspinal origins thwart this mechanism. From the clinical standpoint, these results incite cautiousness in the use of combinations of gabapentin and opioids.

Outcome of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease: correlation with intra-operative multi-unit recordings but not with the type of anaesthesia.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) gained general acceptance in the treatment of Parkinson's disease (PD). OBJECTIVE: To study the clinical outcome and the predicting factors of efficacy of chronic STN stimulation, while DBS electrodes were implanted under local or general anaesthesia with intra-operative electrophysiological guidance based on multi-unit recordings. METHODS: We included a large single-centre cohort of 54 patients with advanced PD (mean age: 59 years; disease duration: 14 years). Clinical evaluation was performed by the Unified Parkinson's Disease Rating Scale (UPDRS) before and 1 year after surgical placement of DBS electrodes. RESULTS: In the on-stimulation and off-medication condition, the UPDRS part III score was reduced by 56% compared to the off-stimulation condition or pre-operative off-drug score. In the on-stimulation and on-medication condition, this score was reduced by 73%. The severity of motor fluctuations and dyskinesia (UPDRS part IV) and the activities of daily living (UPDRS part II) were reduced by 65 and 80%, respectively, in the on-stimulation/on-medication condition compared to the pre-operative baseline. The daily dose of antiparkinsonian treatment was diminished by 72%. Among the various pre- and intra-operative data, the most important predictive factor for clinical efficacy of STN stimulation was the length of hyperactivity along the best track observed in intra-operative multi-unit recordings. Other predictive factors included age, disease duration and pre-operative levodopa responsiveness or baseline off-drug values of the Hoehn and Yahr and UPDRS part III scores. In contrast, the type of anaesthesia (local vs. general) did not significantly influence the clinical outcome. CONCLUSION: The present results are in the average of previously published results, but they have been obtained from a large single-centre cohort of patients with important reductions in the daily dose of antiparkinsonian drugs. This study confirmed the efficacy of the STN-DBS technique and emphasized the value of an original intra-operative electrophysiological approach based on multi-unit and not single-unit quantified recordings. This method allows DBS electrode implantation to be safely performed under general anaesthesia without lessening the rate of efficacy of the procedure.

Somatosensory evoked response and jaw opening reflex elicited by tooth pulp stimulation in awake freely moving rats.

OBJECTIVE: Investigation of pain and nociception refers to different models. Depending upon the intensity of stimulation, unmyelinated pulpal fibers or periodontal A-fibers can be stimulated producing a short or a long latency jaw opening reflex of the digastric muscle. This paper investigates the different components of the jaw opening reflex in addition to the correlation between afferent fibers involved in the cortical evoked response. DESIGN AND SETTING: Fifteen awake male rats were implanted with tooth pulp stimulation electrodes, digastric and cortical recording electrodes. Ten rats were submitted to recordings after a single tooth pulp stimulation, while five rats were using conditioning and test stimulation. Tooth pulp evoked potentials and digastric EMG were simultaneously recorded. A multiresolution denoising method was used for signal processing. RESULTS: Following tooth pulp stimulation, a cortical response was produced including the following peaks: P6.5 +/- 1.1, N11 +/- 1.2, P17 +/- 1.2, P27 +/- 2.9, N53 +/- 7.5, P69 +/- 5.8, P88 +/- 13, N160 +/- 9.7, P204 +/- 14.2. The distribution and amplitude of these peaks are correlated to the stimulation intensity (r=0.96, p<0.01). An interaction between the different components of the jaw opening reflex was identified on EMG, following a conditioning shock, where a cortical evoked response showed a P30 +/- 2.7 peak which was observed concurrently with the jaw opening long latency reflex. CONCLUSION: Our results identify the interaction between the different components of the jaw opening reflex and the correlation to the cortical evoked response.

Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data.

Thirty-two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27.3 months. The first 24 patients were operated according to the technique described by Tsubokawa. The last 13 cases (eight new patients and five reinterventions) were operated by a technique including localisation by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organisation of the motor cortex was established peroperatively by studying the motor responses at stimulation of the motor cortex through the dura. Ten of the 13 patients with central pain (77%) and ten of the 12 patients with neuropathic facial pain had experienced substantial pain relief (75%). One of the three patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zooster. None of the patients developed epileptic seizures. The position of the stimulating poles effective on pain corresponded to the somatotopic representation of the motor cortex. The neuronavigator localisation and guidance technique proved to be most useful identifying the appropriate portion of the motor gyrus. It also allowed the establishment of reliable correlations between electrophysiological-clinical and anatomical data which may be used to improve the clinical results and possibly to extend the indications of this technique.