Galanin-mediated control of pain: enhanced role after nerve injury.

Abstract

The endogenous inhibitory role of the neuropeptide galanin in pain transmission and spinal cord excitability was demonstrated by the use of a high-affinity galanin receptor antagonist, M-35 [galanin-(1-13)-bradykinin-(2-9)-amide]. M-35, which displaced 12'I-labeled galanin from membranes of rat dorsal spinal cord with an IC50 of 0.3 nM, dose-dependently antagonized the effect of intrathecal galanin on the flexor reflex. M-35 potentiated the facilitation of the flexor reflex by conditioning stimulation of cutaneous unmyelinated afferents in rats with intact nerves and the potentiating effect of M-35 on the conditioning-stimulation-induced reflex facilitation of the cutaneous unmyelinated afferents was strongly enhanced after axotomy. These results demonstrate that endogenous galanin plays a tonic inhibitory role in the mediation of spinal cord excitability, and it is particularly noteworthy that this function of galanin is remarkably enhanced after peripheral nerve section.The neuropeptide galanin (1) consists of 29 amino acids, has been shown to occur in a relatively small population of dorsal root ganglion cells and spinal cord interneurons (2-4), and may be involved in sensory modulation. Although some reports indicated that intrathecal (i.t.) galanin has a hyperalgesic effect and i.t. galanin antibody produces analgesia (5), overwhelming evidence suggests that galanin primarily has an inhibitory effect in sensory transmission at the spinal level. Thus, i.t. galanin blocks the facilitatory effect of the flexor reflex produced by the conditioning stimulation (CS) of unmyelinated afferents and by i.t. applied excitatory neuropeptides, such as substance P and calcitonin gene-related peptide (6-8). Galanin also selectively depresses spinal nociceptive reflexes in adult and newborn rats with no or very limited effect on the monosynaptic reflex (6, 9, 10). Galanin (i.t.) has been reported to cause analgesia without motor deficits (11) and iontophresis ofgalanin hyperpolarizes dorsal horn neurons (12). Galanin also inhibits the peripheral consequences of antidromic activation of cutaneous unmyelinated (C) afferents, such as the plasma extravasation, mediated by the release of substance P (13,14).Peripheral axotomy has dramatic effects on peptidergic sensory afferents. Substance P and calcitonin gene-related peptide are downregulated whereas vasoactive intestinal peptide and galanin are upregulated (15)(16)(17)(18)(19)(20). We have recently demonstrated that the vasoactive intestinal peptide level is increased in the same sensory neurons that previously produced substance P (21) and that vasoactive intestinal peptide took over the role of tachykinins as excitatory mediators of nociceptive input (22). We have also shown that the depressive effect of galanin on the flexor reflex is enhanced after nerve section (23) and it antagonized the excitatory effect of vasoactive intestinal peptide, with which it coexists in axotomized sensory neurons (7). Based on these findings, we have hypothesized that one role for upr...

Galanin-receptor ligand M40 peptide distinguishes between putative galanin-receptor subtypes.

“…Fig. 4 also shows that the earlier introduced nonsubtype-specific antagonist M35 in equimolar doses antagonized the effects of galanin on the spinal flexor reflex (28).…”

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

“…Pain behavior in these models is analogous to that observed in a number of human neuropathic pain conditions, including allodynia, hyperalgesia, and expansion of the receptive field. Electrophysiological experiments on axotomized (23,31), chronic constriction injury (32), and spinal nerve ligation (15) animals have shown that intrathecal administration of galanin reduces spinal cord excitability. Furthermore, intrathecal administration of the galanin antagonist M35 (31) significantly potentiates the frequency and severity of axotomy-induced autotomy behavior (33).…”

Expression Cloning of a Rat Hypothalamic Galanin Receptor Coupled to Phosphoinositide Turnover

“…The observation that galanin is also up-regulated in a variety of conditions of neuronal injury has led to the suggestion that galanin may play a role in the pathophysiology of chronic pain and Alzheimer's disease (13,14).…”