Modulation of spinal synaptic transmission by beta-melanocyte stimulating hormone (beta-MSH).

Synaptic modulation refers to altered excitability of a synapse by a substance that does not produce a spike potential at the synapse. Available evidence points to the conclusion that beta-melanocyte stimulating hormone (beta-MSH) modulates synaptic transmission through monosynaptic pathways in the cat spinal cord. Earlier evidence is reviewed, and new data are presented. In the first experiments populations of cells contributing to a knee jerk were studied using the Lloyd preparation, and MSH was found to increase the monosynaptic reflex. With intracellular single unit recording techniques, beta-MSH was found to facilitate recovery from synaptic transmission. With extracellular single unit recording techniques and iontophoretic methods for drug application, beta-MSH has been found to increase the probability of generation of single spike potentials by alpha-motoneurons in response to orthodromic stimulation. Administration of beta-MSH did not cause spontaneous discharge of alpha-motoneurons. The physiological and pharmacological importance of synaptic modulation is discussed.

A fragment of substance P with specific central activity: SP(1-7).

Amino-terminal fragments of substance P (SP), SP(1-7) and SP(1-8), were found to produce naloxone-reversible antinociception in the mouse similar to that produced by SP. Similar to SP, these peptides produce antinociception only within a narrow dose range. They have no activity on smooth muscle or blood pressure. These results suggest that contrary to peripheral effects of SP, which are mediated by receptors which recognize the carboxy-terminal part of the SP molecule, certain central actions of SP are mediated by receptors which recognize the amino-terminal part of the SP molecule. SP may be metabolized to this active fragment prior to its action at these receptors.

Modulation of cat monosynaptic reflexes by substance P.

Substance P (SP) applied by iontophoresis at different current strengths to single motoneurons of cat spinal cord did not cause these units to discharge. SP produced a gradual and prolonged change in synaptic excitability as measured by response to dorsal root stimulation. The effect outlasted application of SP. The lowest effective dose of SP diminished motoneuron response to dorsal root stimulation (inhibitory modulation). Doses 2-4 times as great enhanced the response to dorsal root stimulation (facilitatory modulation) without causing the motoneuron to discharge spontaneously. These observations suggest that one physiological role of SP is modulation of synaptic transmission, i.e. alteration of efficacy of transmission without acting as a primary transmitter at the postsynaptic membrane.

Synaptic modulation by substance P.

The phrase "synaptic modulation," to describe a role of neurotropic peptides, has been used in a number of different ways by a number of different investigators. Using the phrase in its original context, i.e. altered (increased or decreased) synaptic excitability without reference to site or mode of action, evidence is presented that substance P modulates synaptic transmission of cat alpha-motoneurons. The effect appears to be biphasic, with low doses inhibiting, and high doses facilitating synaptic transmission.

Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

The peptide-Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.

An effect of beta-melanocyte stimulating hormone (beta-MSH) on alpha-motoneurones of cat spinal cord.

Actions of beta-MSH and of melatonin on the recovery cycle of single spinal neurones were studied in the decerebrate-spinal cat. beta-MSH facilitated the rate of post-excitation recovery of alpha-motoneurones and some internuncial neurones, and melatonin inhibited the rate of post-excitation recovery. These observations provide additional evidence that beta-MSH functions in the nervous system as a modulator, and may help explain actions of beta-MSH in modifying acquisition of conditioned avoidance responses as well as its interaction with drugs such as morphine.

Influence of peptides on reduced response of rats to electric footshock after acute administration of morphine.

Acute treatment of rats with morphine (10 mg/kg) resulted in a marked reduction of motor response to inescapable electric footshock (EFS). Nalorphine (2mg/kg) antagonized this action of morphine. Pretreatment with synthetic ACTH 1-24 (10 IU) 60 min prior to testing also inhibited this morphine-induced reduction, whereas other ACTH-like peptides, lacking corticotrophic activity, were ineffective. ACTH 1-24 had no effect on the response of adrenalectomized rats to EFS after morphine. In intact rats dexamethasone pretreatment 4 hr prior to testing also antagonized the action of morphine on EFS. Taken together these findings suggest that ACTH 1-24 interferes with the antinociceptive action of morphine and that the integrity of the adrenal is essential for demonstration of this antagonism.

Facilitation of development of resistance to morphine analgesia by desglycinamide9-lysine vasopressin.

Desglycinamide(9)-lysine vasopressin facilitates development of resistance to the analgesic action of morphine in mice if morphine is administered before the peptide. Desglycinamide(9)-lysine vasopressin is not a morphine antagonist, and does not appear to cause either hyperalgesia or alteration of the response to the technique used for evaluating analgesia.