Inhibition of motor system excitability at cortical and spinal level by tonic muscle pain
Introduction
The interaction between pain and motor function is not fully understood, but from daily life we know that deep pain affects movements. Effects of muscle pain on motor control are typically seen as a limited ability to perform movements (Lund et al., 1993).
Several studies have dealt with the effects of cutaneous and subcutaneous painful stimuli on reflexes integrated in the spinal cord (Kranz et al., 1973, Mc Lellan, 1973, Rossi and Decchi, 1995, Inghilleri et al., 1997, Kaneko et al., 1998, Kofler et al., 1998). There is also strong evidence that experimental muscle pain has a modulatory effect on the general motor function in both spinal and trigeminal systems (Lund et al., 1991, Arendt-Nielsen et al., 1996, Svensson et al., 1996, Svensson et al., 1999, Graven-Nielsen et al., 1997a, Westberg et al., 1997, Rossi and Decchi, 1997, Rossi and Decchi, 1999, Matre et al., 1998, Sohn et al., 2000, Wang et al., 2000, Romaniello et al., 2000). On the contrary, little is known about the modulation of nociceptive inputs on motor cortex excitability. In particular, Valeriani et al., 1999, Valeriani et al., 2001 showed that short painful CO2 laser stimuli delivered to the skin of the hand were able to inhibit both the contralateral and ipsilateral primary motor areas (MI). However, the modifications of the motor cortex excitability induced by tonic nociceptive inputs have never been investigated.
The present study was designed to assess whether experimental tonic muscle and subcutaneous pain can modify human motor cortex excitability. Subcutaneous and muscle pain are qualitatively different, thus suggesting that different neural mechanisms subserve these sensations (Graven-Nielsen et al., 1997b). This is confirmed also by neurophysiological and imaging reports (Rossi and Decchi, 1997, Porro et al., 1998). Therefore, it is conceivable that they also have different effects on human motor system. From this point of view, we aimed at investigating whether (i) experimental tonic muscle pain can inhibit the contralateral and/or the ipsilateral motor cortex excitability, and (ii) whether there are differences between the effect of muscle and subcutaneous tonic pain on motor cortex excitability.
In order to reach our purpose we assessed motor system excitability by using the transcranial magnetic stimulation technique (TMS). If the inputs from muscular or subcutaneous nociceptors cause inhibition exclusively at cortical level, the size of the motor evoked potentials (MEP) after TMS should be reduced, while the monosynaptic spinal Hoffman (H)-reflex evoked from the painful muscle should remain unchanged. Indeed, while the TMS excites the pyramidal cells of the motor cortex transynaptically (Di Lazzaro et al., 1998a, Di Lazzaro et al., 1998b), the H-reflex measures the human spinal motoneurones excitability (Schieppati, 1987). Therefore, a differential effect by a conditioning stimulus on MEPs and H-reflex suggests that the observed modulation occurs only at cortical level.
In this study, muscle and subcutaneous tonic pain was induced by injection of hypertonic (5%) saline. This is an effective and standardized method of evoking tonic, reversible pain in humans, as several studies have demonstrated (Stholer and Lund, 1994, Svensson et al., 1995, Graven-Nielsen et al., 1997b).
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Subjects
Healthy, unmedicated subjects, with no history of musculoskeletal pain, participated in the study, which included four experiments: Experiment 1 (n=10, age 23.5±2.7, mean±SD, 7 males and 3 females), Experiment 2 (n=12, age 23.5±2.2, 9 males and 3 females), Experiment 3 (n=12, age 23.3±2.4, 10 males and 2 females), Experiment 4 (n=11, age 26.1±4.8, 8 males and 3 females). 4 subjects participated in all experiments. The subjects were not aware of the purposes of the study. Written informed
Experiment 1: modulation of contralateral motor system excitability by muscle pain (Table 1)
During the injection of the hypertonic saline in the right ADM muscle, the peak-pain on the VAS (5.8±1.3 cm) was found 142±114 s after the injection (Fig. 1A) and was significantly higher than the VAS peak after the injection of isotonic saline in the same muscle (0.5±0.8 cm; Student's t test: P<0.001).
No difference in MEP latencies were found among the 3 stages (baseline, peak- pain and recovery) after painful injection (ANOVA test: F(2,9)=1.05, P=0.23).
During the peak-pain, the MEP amplitudes
The human primary motor area and the spinal motoneurones are inhibited by muscle pain
The main finding of this study is that tonic muscle pain in the hand and forearm resulted in a long-lasting depression of the MEP amplitude after TMS of the primary motor area in the hemisphere contralateral to the painful stimulation. This inhibition was specifically linked to the painful quality of the conditioning stimulation, as the MEP amplitude was not modified when non-painful stimulation was used. During the initial phase of tonic pain, the absence of any effect of muscle pain on the
Conclusions
This is the first study in which an effect of tonic muscle pain on the excitability of the motor cortex has been demonstrated. In particular, we suggest that during tonic muscle painful stimulation, cortico-cortical circuits lead to inhibition of the MI area, which is followed by a later phase of concurrent spinal inhibition. At present, the specific functional significance of our findings cannot be established, but it is clear that the activity from muscle nociceptors can modulate different
Acknowledgements
The present study was supported by the Danish National Research Foundation.
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