Reduction of spinal sensory transmission by facilitation of 5-HT1B/D receptors in noninjured and spinal cord-injured humans

Abstract

Activation of receptors by serotonin (5-HT1) and norepinephrine (α2) on primary afferent terminals and excitatory interneurons reduces transmission in spinal sensory pathways. Loss or reduction of descending sources of serotonin and norepinephrine after spinal cord injury (SCI) and the subsequent reduction of 5-HT1/α2 receptor activity contributes, in part, to the emergence of excessive motoneuron activation from sensory afferent pathways and the uncontrolled triggering of persistent inward currents that depolarize motoneurons during muscle spasms. We tested in a double-blind, placebo-controlled study whether facilitating 5-HT1B/D receptors with the agonist zolmitriptan reduces the sensory activation of motoneurons during an H-reflex in both noninjured control and spinal cord-injured participants. In both groups zolmitriptan, but not placebo, reduced the size of the maximum soleus H-reflex with a peak decrease to 59% (noninjured) and 62% (SCI) of predrug values. In SCI participants we also examined the effects of zolmitriptan on the cutaneomuscular reflex evoked in tibialis anterior from stimulation to the medial arch of the foot. Zolmitriptan, but not placebo, reduced the long-latency, polysynaptic component of the cutaneomuscular reflex (first 200 ms of reflex) by ∼50%. This ultimately reduced the triggering of the long-lasting component of the reflex (500 ms poststimulation to end of reflex) known to be mediated by persistent inward currents in the motoneuron. These results demonstrate that facilitation of 5-HT1B/D receptors reduces sensory transmission in both monosynaptic and polysynaptic reflex pathways to ultimately reduce long-lasting reflexes (spasms) after SCI.

Fig. 1.

H-reflexes after zolmitriptan in uninjured control and spinal cord-injured (SCI) participants. A: M-wave (M) and maximum H-reflex (H_max) recorded in a single uninjured control participant before (black trace) and 120 min after (gray trace) 10 mg of zolmitriptan. B: corresponding H-reflex and M-wave recruitment curve from same participant in A plotted peak to peak and normalized to M_max. Stimulation intensity is expressed as a multiple of motor threshold. The 2 predrug H-wave recruitment curves (Pre1&2) are represented by black lines and solid circles, the 30-min curve by a dark gray line and open circles, the 90-min curve by a light gray line and solid triangles, and the 120 min curve by a dark gray line and open triangles (data at 60 min not shown for clarity). M-wave recruitment curves have similar line colors but with no symbols for clarity. C and D: similar to A and B but for a T3–T4 SCI participant (subject 2M in Table 1).

Fig. 2.

Group data: H_max and M_max after zolmitriptan. A, top: averaged H_max, expressed as a percentage of predrug values, at 30, 60, 90, and 120 min after zolmitriptan (open circles) and placebo (Plb; filled circles) intake in 6 uninjured control participants. Bottom, average M_max expressed as a percentage of predrug values at all time points after zolmitriptan (open circles) and placebo (filled circles). B: same as in A but for averaged data across the 7 SCI participants. C: peak decrease in H_max, expressed as a percentage of predrug values, irrespective of time after zolmitriptan intake for both uninjured control (open bar) and SCI participants (filled bar). D: averaged H_max, expressed as a percentage of predrug values, for 3 uninjured control participants receiving placebo (filled circles, black line), 5 mg of zolmitriptan (filled circles, gray line), and 10 mg of zolmitriptan (open circles, gray line), respectively. Error bars represent means ± SE. *P < 0.05; **P < 0.01; ***P < 0.005.

Fig. 3.

Zolmitriptan and CMR in SCI participants. A: overlay of 6 unrectified tibialis anterior (TA) EMG traces before (top traces) and after 10 mg of zolmitriptan (bottom traces) in a single C6–C7 SCI participant (subject 5M in Table 1). Gray bar denotes the window calculated for the long polysynaptic reflex (LPR; start of reflex to 300 ms), and black bar denotes the long-lasting reflex (LLR; 500 ms poststimulation to end of reflex). B: similar to A but for C6–C7/L3 SCI participant (subject 4F in Table 1). C: averaged LPR, expressed as a percentage of predrug values, at 30, 60, 90, and 120 min after 10 mg of zolmitriptan (open circles) and placebo (filled circles) in 6 of the 7 SCI participants (subjects 1M–6M in Table 1). D: same as in C but for the LLR in 5 of the 7 SCI participants (subjects 1M–5M in Table 1). Error bars represent means ± SE. *P < 0.05; **P < 0.01; ***P < 0.005.

Fig. 4.

Effects of zolmitriptan verified in a rat model of SCI. A: monosynaptic reflex (Mono) recorded from a ventral root of a chronically spinalized rat that did not display a polysynaptic reflex response. B: monosynaptic reflex from A following 300 nM bath application of zolmitriptan (+Zolm). C: short-latency polysynaptic reflex (SPR) recorded from a ventral root of a different chronically injured rat (no monosynaptic response was evoked). D: polysynaptic reflex from C after 300 nM application of zolmitriptan (modified from Fig. 5 in Murray et al. 2011). E and F: overlays of 6 SPRs recorded from TA in a SCI participant (subject 3M in Table 1) before (E) and 120 min after (F) 10 mg of oral zolmitriptan. In A–F, asterisks mark time of single pulse, or start of multiple pulse, stimulation.

Fig. 5.

Target sites for antispastic drugs. Presynaptic (1), motoneuron (2), and GABAergic (3) sites of action for antispastic drugs are depicted. Site 1: GABA_b, α₂, and 5-HT₁ receptors (r) located on presynaptic sensory terminals or on pre- or postsynaptic sites on interposed excitatory interneurons activated by baclofen, tizanidine, and zolmitriptan, respectively, to reduce glutamate release and activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors on motoneuron. Site 2: 5-HT₂/α₁ receptors on motoneuron with constitutive or ligand activation, which facilitates downstream voltage-gated calcium channels (CaV) mediating PICs via G_q protein-coupled pathways. Inverse agonists switch the 5-HT₂/α₁ receptors into their inactive states to reduce activity in the G_q pathway, lessen facilitation of CaV receptors, and reduce PICs and, consequently, muscle spasms. Site 3: spinal injection of the HIV1-CMV-GAD65 lentivirus leads to an increase in GAD65 gene expression and GABA release from astrocytes. Combined systemic administration of tiagabine, a GABA reuptake inhibitor, increases levels of GABA to a sufficient level to activate pre- and postsynaptic GABA receptors to reduce spasticity. Cypro, cyproheptadine.