Nauropharmacology,
1978, 17, 153-156.
Pergamon
Press.
PRELIMINARY STIMULANT
ACTION
OF THYROTROPIN
Barrett
in Great Britain
NOTES
RELEASING
R. Cooper
Printed
HORMONE
and Charles
ON CAT SPINAL
CORD
E. Boyer
Department of Pharmacology Wellcome Research Laboratories Redearch Triangle Park, N.C. 27709
(Accepted
11 November
19771
Thyrotropin releasing hormone (TRH) produced a rapid dose SUMMARY related elevation of muscle tonus accompanied by tremor and shiveringThis stimulant action of TRH also occurred like movements in cats. in decerebrate cats and cats which had undergone spinal cord transection at the level of the first cervical vertebra. Recordings from spinal cord ventral roots indicated that TRH induced a pronounced No such increase in spontaneous motor neuron action potentials. stimulation of muscle activity was produced by injections of thyrotropin (TSH), triiodothyronine (T ), deamidated TRH, or the constituent amino acids of TRH, pyroglu ?amic acid, histidine, and proline amide. Results suggest that TRH can act directly on the spinal cord to stimulate muscle activity via a nonendocrine mechanism.
Thyrotropin releasing hormone (TRH, 1-pyroglutamyl-1-histidyl-1-proline amide) is known to be a releaser of thyrotropin (TSH) and prolactin (Bowers, Friesen, Hwang, Gllyda and In addition to these actions, TRH has also been found to have behavioral Folkers, 1971). effects in both animals and man (Breese, Cott, Cooper, Prange, Lipton and Plotnikoff, 1975; Prange, Wilson, Lara, Alltop and Breese, 1972; Wei, Segal and Way, 1975) suggesting that the role of this tripeptide in CNS function is not limited to its neuroendocrine activity. Consistent with this view are recent findings that more than one half of the content of TRH in brain is localized in tissue other than the hypothalamus (Winokur and Utiger, 1974). Electrophysiological evidence that TRH can depress the firing of single cortical neurons in mammals (Renaud and Martin, 1975) or produce an excitatory effect on motor neurons in frog spinal cord (Nicoll, 1977) suggests that this peptide can alter or modulate neural activity. We will report here evidence that TRH in the cat stimulates the spinal cord to elevate skeletal muscle tonus and to produce high frequency tremor or shivering-like movements. In pilot studies with restrained, conscious cats, we found that TRH (2 mg/kg i.v.) produced a generalized increase in muscle tonus as evidenced by an activation of electromyographic (JZMG) activity in both flexor and extensor muscle groups. Additional preliminary experiments to identify the site of action for EXG effects revealed that TRH also increased the amplitude and frequency of the EMG recorded from various muscle groups in cats after midcollicular decerebration. These findings prompted the present work to be reported in detail in this communication, which was performed in "spinal cats" with the spinal cord transected anterior to the first cervical vertebra. Each animal was anesthetized with sodium thiopental (30 mg/kg i.v.) and respiration was maintained using an artificial respirator. The carotid arteries were ligated and vertebral arteries were clamped, eliminating the blood supply to the pituitary and the brain. The spinal cord was then severed just anterior to the first cervical vertebra, and at least 2 hours were allowed for the animal to recover from thiopental and surgical trauma prior to beginning an experiment. In some cats, a laminectomy and bilateral rhizotomy were performed so that direct recordings could be made from the L ventral root. Temperature was maintained at 37°C by a thermostatically regulated heat la$p. Figure 1 shows the characteristic electromyographic activity produced by TRH (2 mg/kg i.v.) in the spinal cat. The elevation of muscle tonus occurred within 10 sec. of injection and lasted for approximately 30 min. Observation of spinal animals receiving TRH during the experiment revealed that this tripeptide produced intermittently both flexion and extension of limbs, tremor or shiver-like high frequency movements and some fasciculation-like activity of the musculature of the thorax. This skeletal muscle activation was dose related, as shown in Table 1. In some spinal cats, brief penile erection and pelvic thrusting were elicited
153
Preliminary
154
Notes
and occasional digging-like motions of the forelimbs were seen, occurring within 5 min. of Responses involving gross body movements were more reliably injection of the 2 mg/kg dose. Rapid development of tolerance to reobtained following higher doses of TRH (5.0 mg/kg). peated injections of TRH was also observed, often being complete after 4 injections at the Marked changes in blood pressure or 2 mg/kg dose when injections were spaced 30 min. apart. heart rate did not occur (see Fig. 1 for representative blood pressure record). s
1978, 17, 153-156.
Pergamon
Press.
PRELIMINARY STIMULANT
ACTION
OF THYROTROPIN
Barrett
in Great Britain
NOTES
RELEASING
R. Cooper
Printed
HORMONE
and Charles
ON CAT SPINAL
CORD
E. Boyer
Department of Pharmacology Wellcome Research Laboratories Redearch Triangle Park, N.C. 27709
(Accepted
11 November
19771
Thyrotropin releasing hormone (TRH) produced a rapid dose SUMMARY related elevation of muscle tonus accompanied by tremor and shiveringThis stimulant action of TRH also occurred like movements in cats. in decerebrate cats and cats which had undergone spinal cord transection at the level of the first cervical vertebra. Recordings from spinal cord ventral roots indicated that TRH induced a pronounced No such increase in spontaneous motor neuron action potentials. stimulation of muscle activity was produced by injections of thyrotropin (TSH), triiodothyronine (T ), deamidated TRH, or the constituent amino acids of TRH, pyroglu ?amic acid, histidine, and proline amide. Results suggest that TRH can act directly on the spinal cord to stimulate muscle activity via a nonendocrine mechanism.
Thyrotropin releasing hormone (TRH, 1-pyroglutamyl-1-histidyl-1-proline amide) is known to be a releaser of thyrotropin (TSH) and prolactin (Bowers, Friesen, Hwang, Gllyda and In addition to these actions, TRH has also been found to have behavioral Folkers, 1971). effects in both animals and man (Breese, Cott, Cooper, Prange, Lipton and Plotnikoff, 1975; Prange, Wilson, Lara, Alltop and Breese, 1972; Wei, Segal and Way, 1975) suggesting that the role of this tripeptide in CNS function is not limited to its neuroendocrine activity. Consistent with this view are recent findings that more than one half of the content of TRH in brain is localized in tissue other than the hypothalamus (Winokur and Utiger, 1974). Electrophysiological evidence that TRH can depress the firing of single cortical neurons in mammals (Renaud and Martin, 1975) or produce an excitatory effect on motor neurons in frog spinal cord (Nicoll, 1977) suggests that this peptide can alter or modulate neural activity. We will report here evidence that TRH in the cat stimulates the spinal cord to elevate skeletal muscle tonus and to produce high frequency tremor or shivering-like movements. In pilot studies with restrained, conscious cats, we found that TRH (2 mg/kg i.v.) produced a generalized increase in muscle tonus as evidenced by an activation of electromyographic (JZMG) activity in both flexor and extensor muscle groups. Additional preliminary experiments to identify the site of action for EXG effects revealed that TRH also increased the amplitude and frequency of the EMG recorded from various muscle groups in cats after midcollicular decerebration. These findings prompted the present work to be reported in detail in this communication, which was performed in "spinal cats" with the spinal cord transected anterior to the first cervical vertebra. Each animal was anesthetized with sodium thiopental (30 mg/kg i.v.) and respiration was maintained using an artificial respirator. The carotid arteries were ligated and vertebral arteries were clamped, eliminating the blood supply to the pituitary and the brain. The spinal cord was then severed just anterior to the first cervical vertebra, and at least 2 hours were allowed for the animal to recover from thiopental and surgical trauma prior to beginning an experiment. In some cats, a laminectomy and bilateral rhizotomy were performed so that direct recordings could be made from the L ventral root. Temperature was maintained at 37°C by a thermostatically regulated heat la$p. Figure 1 shows the characteristic electromyographic activity produced by TRH (2 mg/kg i.v.) in the spinal cat. The elevation of muscle tonus occurred within 10 sec. of injection and lasted for approximately 30 min. Observation of spinal animals receiving TRH during the experiment revealed that this tripeptide produced intermittently both flexion and extension of limbs, tremor or shiver-like high frequency movements and some fasciculation-like activity of the musculature of the thorax. This skeletal muscle activation was dose related, as shown in Table 1. In some spinal cats, brief penile erection and pelvic thrusting were elicited
153
Preliminary
154
Notes
and occasional digging-like motions of the forelimbs were seen, occurring within 5 min. of Responses involving gross body movements were more reliably injection of the 2 mg/kg dose. Rapid development of tolerance to reobtained following higher doses of TRH (5.0 mg/kg). peated injections of TRH was also observed, often being complete after 4 injections at the Marked changes in blood pressure or 2 mg/kg dose when injections were spaced 30 min. apart. heart rate did not occur (see Fig. 1 for representative blood pressure record). s
