Flexor Reflex In Rats Research Articles

The effect of intrathecal selective agonists of Y 1 and Y 2 neuropeptide Y receptors on the flexor reflex in normal and axotomized rats

We have examined the effects of intrathecal (i.t.) administration of [Leu 31,Pro 34]-neuropeptide Y (NPY) or NPY-(13–36), selective agonists of NPY Y 1 or Y 2 receptors, respectively, on the excitability of the flexor reflex in normal rats and after unilateral transection of the sciatic nerve. In rats with intact and sectioned sciatic nerves, i.t. [Leu 31,Pro 34]-NPY induced a similar biphasic effect on the flexor reflex with facilitation at low doses and facilitation followed by depression at high doses. In contrast, i.t. NPY-(13–36) only facilitated the flexor reflex in normal rats, and at high dose it caused ongoing discharges in the electromyogram. NPY-(13–36) caused dose-dependent depression of the flexor reflex in rats after sciatic nerve transection, in addition to its facilitatory effect. Topical application of [Leu 31,Pro 34]-NPY or NPY-(13–36) caused a moderate and brief reduction in spinal cord blood flow. No difference was noted between the vasoconstrictive effect of [Leu 31,Pro 34]-NPY and NPY-(13–36). It is suggested that activation of Y 1 receptors may be primarily responsible for the reflex depressive effect of i.t. neuropeptide Y in rats with intact sciatic nerves, whereas both Y 1 and Y 2 receptors may be involved in mediating the depressive effect of NPY after axotomy.

Involvement of endogenous opioids and ATP-sensitive potassium channels in the mediation of apomorphine-induced antinociception at the spinal level: a study using EMG planimetry of flexor reflex in rats

The effects of intrathecally (i.t.) administered naloxone or glibenclamide, a blocker of adenosine triphosphate-sensitive potassium (K ATP) channels, on the antinociception produced by i.t. apomorphine were observed by an integrated electromyogram measurement of hindlimb flexor reflex in lightly pentobarbital-anesthetized rats. The results showed that i.t. apomorphine produced a significant and dose-dependent antinociception and that the antinociception produced by i.t. apomorphine could be blocked dose dependently by i.t. naloxone or glibenclamide. The results suggest that endogenous opioids and ATP-sensitive potassium channels might be sequentially involved in the mediation of apomorphine-induced antinociception at the spinal level.

The effect of intrathecal neuropeptide Y on the flexor reflex in rats after carrageenan-induced inflammation

We examined the effects of intrathecal (i.t.) administration of neuropeptide Y (NPY) on the excitability of the flexor reflex in normal rats and 24 h after inflammation induced by subcutaneous carrageenan. In normal rats, i.t. NPY at low doses (10 and 100 ng) caused a brief facilitation of the flexor reflex with no subsequent depression. At higher doses (1 and 10 μg), the effect of NPY was mainly inhibitory, causing substantial and usually prolonged depression of the flexor reflex. At 24 h after the injection of carrageenan, when inflammation was at its peak, the magnitude of the reflex was increased and discharge duration became prolonged. I.t. NPY produced similar pattern of dose-dependent facilitatory and depressive effects on the flexor reflex. The facilitatory effect of i.t. NPY, particularly for the higher doses, was significantly enhanced in inflamed rats compared to normals. In contrast, the depressive effect of high doses of i.t. NPY was unchanged. These data suggest that the changes in levels of NPY and NPY receptors in the spinal cord known to occur after inflammation, are associated with an increased excitatory effect of this peptide.

Phe1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2, a proposed antagonist of the nociceptin receptor, is a potent and stable agonist in the rat spinal cord

[Phe 1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2 is an nociceptin analogue which has been shown to be a selective antagonist of the nociceptin receptor in peripheral tissues. We now report that intrathecal [Phe1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2 produced a dose-dependent depress ion of the nociceptive flexor reflex in rats. an effect that is similar to nociceptin. The duration of depression produced by [Phe 1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2 was significantly more prolonged than by nociceptin. The reflex depressive effect of nociceptin was not blocked by [Phe 1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2. The results indicated that the proposed nociceptin receptor antagonist [Phe 1 Ψ(CH 2-NH)Gly 2]-nociceptin-(1-13)NH 2 is a potent agonist in rat spinal cord and more resistant to enzymatic degradation compared to nociceptin.

ATP-Sensitive K Channels are Involved in the Mediation of Intrathecal Norepinephrine- or Morphine-Induced Antinociception at the Spinal Level: A Study Using EMG Planimetry of Flexor Reflex in Rats

The effects of intrathecally ( IT ) administered glibenclamide (Gli), an ATP-sensitive K + (K ATP) channel blocker, on the antinociception produced by IT norepinephrine (NE), serotonin (5-HT), morphine (Mor), or adenosine agonist, 5′- N -ethylcarboxamide adenosine (NECA) were investigated using integrated EMG measurement of hindlimb flexor reflex (FR) in lightly pentobarbital-anesthetized rats. The results showed that: 1) NE (3, 6, or 12 nmol) or 5-HT (60, 120, or 240 nmol) each produced a dose-dependent suppression of FR EMG, respectively; 2) pretreatment with Gli (5, 10, or 20 nmol) antagonized the NE (6 nmol)-induced antinociception in a dose-dependent manner and failed to modulate the 5-HT (120 nmol)-induced suppression of FR EMG; 3) pretreatment with Gli (5, 10, or 20 nmol) also antagonize the Mor (2 nmol)-induced suppression of FR EMG in a dose-dependent manner; 4) pretreatment with naloxone (Nal, 60, 120, or 240 nmol) also antagonize the NE (6 nmol)-induced suppression of FR EMG in a dose-dependent manner; and 5) NECA (0.5, 1.0, or 2.0 nmol) produced a dose-dependent suppression of FR EMG, while pretreatment with Gli (5, 10, or 20 nmol) failed to modulate the NECA (1.0 nmol)-induced suppression of FR EMG. The results show that (a) ATP-sensitive K + channels are involved in the NE- and Mor-induced antinociception but not 5-HT- or NECA-induced antinociception at the spinal level; (b) endogenous opioids might act as a successor of NE and then activate K ATP channels to producing the antinociception.

The effect of naturally occurring fragments of galanin message-associated peptide on spinal cord excitability in rats

Galanin message-associated peptide (GMAP), a 60 amino acid fragment of galanin precursor protein, is present in dorsal root ganglion cells and upon intrathecal (i.t.) administration influences the spinal nociceptive flexor reflex in rat in a complex manner. The present study assessed the effects on spinal cord excitability of N-terminal fragment GMAP (1–30) and C-terminal fragments GMAP (34–60) or GMAP (35–60), which were formed from GMAP following enzymatic degradation. The effect of the fragments was compared with the effects of the complete peptide sequence. The GMAP fragments slightly facilitated the flexor reflex and dose-dependently blocked hyperexcitability following C-fiber conditioning stimulation. The potency of the blocking effect of GMAP(1–30) was comparable to GMAP(1–60) and was one order of magnitude higher than the potency of the C-terminal fragments. The results indicated that both naturally formed N- and C-terminal fragments of GMAP are pharmacologically active and produce effects which are similar to the full peptide sequence.

Spinal NK 2 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation

The role of endogenous neurokinin A in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation was examined by determining the effect of a selective NK 2 receptor antagonist, GR103537, on the nociceptive flexor reflex in rats. Intrathecal administration of GR103537 (1.4–14 nmol) dose-dependently attenuated the increased activity of the flexor reflex ipsilateral to the inflamed paw. The activity of GR103537 at NK 2 receptors was confirmed by blockade of the facilitation of the reflex by neurokinin A but not substance P in normal rats. These results indicate that endogenous neurokinin A increases the excitability of spinal neurons during persistent peripheral inflammation.

Fragments of galanin message-associated peptide (GMAP) modulate the spinal flexor reflex in rat

We have previously reported that galanin message-associated peptide (GMAP), a fragment of galanin precursor protein, is present in dorsal root ganglion cells and upon intrathecal (i.t.) administration influences the spinal nociceptive flexor reflex in a complex manner in the rat. GMAP elicited a moderate facilitation of the flexor reflex, but when administered prior to conditioning stimulation of C-afferents, it dose dependently blocked spinal cord hyperexcitability. The present study examined the effects of four fragments of GMAP-(1-60), GMAP-(1–12), GMAP-(10–24), GMAP-(25–44) and GMAP-(37–60), on the flexor reflex and compared them with the effects of the complete peptide sequence. All four GMAP fragments facilitated the flexor reflex. However, this effect was dose-dependent only for GMAP-(1–12) and the effect of GMAP-(1–12) was stronger than GMAP-(1–60). In contrast, only GMAP-(25–44) dose dependently blocked the facilitation of the flexor reflex induced by the C-fiber conditioning stimulation. The potency of the blocking effect of GMAP-(25–44) was one order of magnitude lower than that of GMAP-(1–60). The results indicated that two fragments of GMAP are pharmacologically active and produce effects which are similar to the full sequence. It is possible that the complex effect of GMAP may be mediated by different subtypes of GMAP receptors which recognize different portions of the GMAP sequence.

The effects of intrathecal galanin message-associated peptide (GMAP) on the flexor reflex in rats

We have examined the effects of intrathecal (i.t.) galanin message-associated peptide (GMAP), the C-terminal flanking peptide in the galanin (GAL) precursor protein, which is produced in equimolar quantities with galanin and which is upregulated upon axotomy, on the spinal nociceptive flexor reflex in decerebrate, spinalized, unanesthetized rats. I.t. GMAP elicited a moderate facilitation of the flexor reflex. No depression of baseline flexor reflex was observed with any dose of GMAP. The facilitation of the flexor reflex induced by conditioning stimulation (CS) of cutaneous C-afferents was dose-dependently blocked by GMAP. The reflex facilitatory effect of exogenously applied substance P (SP), one of the endogenous modulators of reflex hyperexcitability following C-fiber CS, was only blocked by GMAP at a relatively high dose. I.t. GMAP did not antagonize the reflex facilitatory effect of vasoactive intestinal peptide and did not potentiate the reflex depressive effect of i.t. morphine or clonidine. Finally, 1 μg i.t. GMAP did not influence spinal cord blood flow whereas 10 μg GMAP induced a transient decrease in spinal cord blood flow in some experiments. The ability of GMAP to block the increase in spinal cord excitability following repetitive C-fiber stimulation may be through a presynaptic action. Although some of the effects of GMAP were similar to galanin, distinct differences were found, particularly in interaction with other excitatory and inhibitory agents. It is possible that GMAP exerts its action in the spinal cord through its own specific receptor. GMAP may act similarly to GAL in some, but not all pharmacological functions. The present results could thus represent another example where different peptides arising from the same peptide precursor produce differential pharmacological actions.

Peripheral axotomy increases the expression of galanin message-associated peptide (GMAP) in dorsal root ganglion cells and alters the effects of intrathecal GMAP on the flexor reflex in the rat

We have previously reported that galanin message-associated peptide (GMAP), a fragment of galanin precursor protein, occurs in a limited number of dorsal root ganglion (DRG) cells in rats with intact sciatic nerves. In the present study, the localization of GMAP in dorsal root ganglia, dorsal roots and dorsal horn was analyzed immunohistochemically and compared between rats with intact and sectioned sciatic nerves. Furthermore, the effects of intrathecal (i.t.) GMAP on the flexor reflex in rats with intact and sectioned nerves were examined. In rats with intact sciatic nerves, i.t. GMAP elicited a moderate facilitation of the flexor reflex. The facilitation of the flexor reflex induced by conditioning stimulation (CS) of cutaneous C-fibers was strongly blocked by GMAP. GMAP also selectively antagonized the reflex facilitatory effect of i.t. substance P (SP), but not i.t. vasoactive intestinal peptide (VIP). Unilateral sciatic nerve section induced an upregulation of GMAP in the ipsilateral dorsal root ganglia 2 weeks after axotomy. The effect of GMAP on the baseline reflex was similar in normal and axotomized rats, but the blocking effect of GMAP on C-fiber CS-induced facilitation was significantly reduced after axotomy. GMAP did not antagonize the reflex facilitatory effect of SP after axotomy, whereas an antagonism on VIP-induced facilitation was observed. The possible role of GMAP in spinal transmission and comparison with the effects of galanin are discussed.

Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants

Some novel 2-methyl-3-aminopropiophenones were synthesized and their centrally acting muscle relaxant activities were evaluated for an inhibitory effect on the flexor reflex in rats. The structure-activity relationships are discussed. In this series, 2-methyl-3-pyrrolidino-1-(4-trifluoromethylphenyl)-propan-1-one ( 28 ) showed significant centrally acting muscle relaxant activity. In addition, the activities of each enantiomer ( 28 -( S ) and ( R ) were studied along with their acute toxicities. Compound 28 -( R ) was found to exhibit more potent activity and weaker acute toxicity than 28 -( S ). Accordingly, compound 28 -( R ) (NK433) is under development as a novel centrally acting muscle relaxant.

The effects of intrathecal neuropeptide Y on the spinal nociceptive flexor reflex in rats with intact sciatic nerves and after peripheral axotomy

We examined the effects of intrathecally administered neuropeptide Y on the spinal nociceptive flexor reflex in decerebrate, spinalized, unanesthetized rats with intact sciatic nerves, or 11–39 days after unilateral transection of the sciatic nerve. In rats with intact sciatic nerve, intrathecal neuropeptide Y at low doses (10 and 100ng) caused a brief facilitation of the flexor reflex. At a dose of 300 ng, the effect of neuropeptide Y on the flexor reflex was biphasic i.e. a brief facilitation followed by slight depression. At higher doses (1 and 10 μg), the effect of neuropeptide Y was mainly inhibitory, causing substantial and usually prolonged depression of the flexor reflex magnitude. The reflex depression caused by intrathecal neuropeptide Y was not reversed by the opioid antagonist naloxone or theα 2 adrenoceptor antagonist atipamezole. Intrathecal neuropeptide Y at doses up to 1 and 10μg had no effect on reflex facilitation caused by conditioning stimulation of C-fibers, intrathecal substance P or neurokinin A. Topical application of neuropeptide Y (1 μg/μl) failed to influence the monosynaptic reflex in normal rats. Eleven to 16 days after peripheral axotomy, the initial excitation of the flexor reflex to intrathecal neuropeptide Y was significantly enhanced in axotomized compared with normal rats. However, the depressive effect of neuropeptide Y on the flexor reflex was unchanged. Neuropeptide Y did not influence the monosynaptic reflex in axotomized rats at this period. In experiments performed on rats in which the sciatic nerve had been transected 31–39 days previously, the facilitatory effect of neuropeptide Y on the flexor reflex remained enhanced compared with normal rats. Furthermore, the inhibitory effect of neuropeptide Y also increased as 100 ng intrathecal neuropeptide Y was able to produce reflex depression in a similar fashion as 300 ng neuropeptide Y normally and the reflex depression caused by 1 μg neuropeptide Y was stronger and longer lasting than in normal rats. Intrathecal neuropeptide Y (100 ng-10 μg) in rats with intact sciatic nerves caused a moderate decrease in spinal cord dorsal surface blood flow as measured with a laser Doppler flowmeter. This effect of neuropeptide Y was unchanged in axotomized rats. The present results support previous observations that spinal application of neuropeptide Y in normal rats caused antinociception. As the depressive effect of neuropeptide Y is independent of spinal opioid andα 2-adrenergic systems, it may be mediated by its own receptors. The biphasic effect of neuropeptide Y may reflect its action on different subtypes of neuropeptide Y receptors. Experiments with neuropeptide Y receptor antagonists are required to further define the role of endogenous neuropeptide Y in nociception normally and after peripheral axotomy.

The spinal analgesic role of α2-adrenoceptor subtypes in rats after peripheral nerve section

Two putative agonists of subtypes of α 2-adrenoceptors, guanfacine ( α 2A) and ST-91 (2-[2,6-dicthylphenylaminol]-2-imidazoline, α 2C), were applied intrathecally and their effects on autotomy behaviour and on the flexor reflex before and after sciatic nerve section were examined. Neither drug influenced autotomy during a 17-day observation period. Both drugs dose dependently depressed the flexor reflex in rats with intact sciatic nerves. After axotomy, the sensitivity of the flexor reflex to guanfacine and ST-91 was moderately increased compared to normals. ST-91 i.t. at high doses evoked motor discharges, an effect which was reversed by the α 1-adrenoceptor antagonists, WB4101 (2-[2,6-dimethoxyphenoxyethyl]-aminomethyl-1,4-benzodioxane). Thus, the effect of i.t. clonidine on the flexor reflex and autotomy behaviour observed previously may not involve its action on α 2A- and α 2C-adrenoceptors. Furthermore, due to its motor effect which may involve activation of α 1-adrenoceptors, ST-91 may not be a suitable tool to study the physiological function of spinal α 2C-adrenoceptors.

The CCK-B antagonist CI988 enhances the reflex-depressive effect of morphine in axotomized rats.

We have examined and compared the effect of systemic CI988, an antagonist of the cholecystokinin B receptor, and morphine on the flexor reflex in rats with intact sciatic nerves and after unilateral axotomy. Intravenous injection of 1 mg kg-1 morphine caused a moderate depression of the flexor reflex in normal and axotomized rats. The duration of morphine-induced depression was significantly shortened in axotomized animals. In contrast, the brief depressive effect of intravenous CI988 on the flexor reflex was significantly enhanced in axotomized rats. Combination of morphine and CI988 resulted in a significant potentiation of reflex depression in rats with intact or sectioned sciatic nerves. It is concluded that blockade of CCK-B receptor potentiated morphine-induced antinociception in rats after peripheral nerve injury.

Pentamidine, an inhibitor of spinal flexor reflexes in rats, is a potent [formula omitted] (NMDA) antagonist in vivo

The present study examined whether the antimicrobial agent pentamidine exerts an antagonistic action at the N- methyl- d-aspartate (NMDA) receptor as tested on spinal reflexes in rats in vivo. After intrathecal injection both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and pentamidine dose-dependently reduced the magnitude of the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of pentamidine on the flexor reflex was prevented by coadministration with NMDA but not with the non-NMDA agonist α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. These data suggest that pentamidine exerts an antagonistic action at the NMDA receptor in vivo.

The effect of intrathecal guanfacine and clonidine on the flexor reflex in rats with intact and sectioned sciatic nerves

We examined the effect of intrathecal (i.t.) administration of the non-selective α 2-adrenoceptor agonist clonidine and the α 2A- adrenoceptor selective agonist guanfacine on flexor reflex excitability in decerebrate, spinalized, unanesthetized rats before and after unilateral section of the sciatic nerve. Both guanfacine and clonidine dose dependently depressed the flexor reflex in rats with intact nerves. There was a dramatic increase in the sensitivity of the flexor reflex to the depressive effect of i.t. clonidine 4 to 18 days after sciatic nerve section. In contrast, the sensitivity to i.t. guanfacine increased only slightly. The present results suggest that the markedly increased sensitivity to the analgesic effect of the non-selective α 2-adrenoceptor agonist does not involve up-regulation of α 2A- adrenoceptors . Since radioligand binding data suggested that about 4% of spinal cord α 2- adrenoceptors are of the α 2C type, whereas α 2B- adrenoceptors are not detectable. α 2C- adrenoceptors seem to be a good candidate to mediate the up-regulated response to clonidine in axotomized rats. Thus, α 2C- adrenoceptor agonists may be useful in the treatment of neuropathic pain.

The effects of tianeptine on wet-dog shakes, fore-paw treading and a flexor reflex in rats are consistent with enhancement of 5-hydroxytryptamine uptake

Tianeptine is a novel antidepressant which uniquely facilitates 5-hydroxytryptamine (5-HT) uptake. When given in a dose of 10 mg/kg to rats pretreated with either carbidopa or phenelzine, it markedly reduced the frequency of wet-dog shakes, fore-paw treading, tremor and hind-limb abduction evoked by L-5-hydroxytryptophan (L-5-HTP) given 30 or 60 min later. This effect of tianeptine was opposite to that of paroxetine, a selective 5-HT uptake inhibitor, which greatly increased the 5-HTP-induced behavioural syndrome. In contrast, tianeptine did not affect behaviours elicited by the 5-HT receptor agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), which are not substrates for the 5-HT uptake process. In spinal animals, tianeptine attenuated an ipsilateral flexor reflex, an effect opposite to that of citalopram, a selective 5-HT uptake inhibitor. These effects of tianeptine are consistent with its ability to increase 5-HT reuptake. Tianeptine; L-5-Hydroxytryptophan (L-5-HTP); 5-HT behavioural syndrome; 5-HT uptake inhibition; Flexor reflex; Paroxetine

The specific antagonistic effect of intrathecal spantide II on substance P- and C-fiber conditioning stimulation-induced facilitation of the nociceptive flexor reflex in rat

The effect of intrathecally (i.t.) applied tachkykin antagonist d-NicLys 1, 3-Pal 3, d-Cl 2Phe 5, Asn 6, d-Trp 7,9, Nle 11-substance P (SP), spantide II, on the nociceptive flexor reflex was studied in decerebrate, spinalized, unanaesthesized rats over the dose rangfe of 10 ng-10μg. I.lt. spantide II usually caused weak facilitation of the flexor reflex, especially at lower doses (10–100 ng) and at higher doses (1–10 μg) it sometimes depressed the reflex. Pre-treatment with spantide II (1, 3 or 10 μg) effectively antagonized the facilitatory effect of 10 ng i.t. SP on the flexor reflex for about 30 min. The facilitation of the reflex induced by i.t. administration of other neuropeptides present in primary afferents, somatostatin (SOM), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and galanin (GAL), was not influenced by spantide II. This non-toxic antagonist also effectively blocked facilitation of the flexor reflex induced by C-fiber conditioning stimulation of the sural nerve. The present results indicate that spantide II is an effective tachykinin antagonist in the spinal cord. Furthermore, C-fiber stimulation facilitates the nociceptive flexor reflex through a mechanism involving the release of SP from the central terminals of primary afferents.

The N-terminal 1–16, but not C-terminal 17–29, galanin fragment affects the flexor reflex in rats

The biological activity of two galanin (GAL) fragments, GAL-(1–16) and GAL-(17–29), was tested in vivo by using a spinal nociceptive flexor reflex model in the rat. Intrathecal (i.t.) GAL-(1–16) had a similar biphasic effect on the flexor reflex, with facilitation at lower doses and facilitation followed by depression at higher doses, as the full length peptide GAL-(1–29). GAL-(1–16) also effectively depressed the facilitation of the flexor reflex caused by i.t. substance P (SP) or C-fiber conditioning stimulation (CS) and potentiated the depressive effect of i.t. morphine on the reflex, both actions that have been reported earlier with GAL-(1–29). In contrast, i.t. GAL-(17–29), even at high doses, did not induce changes in the amplitude of the flexor reflex, nor did it interact with the effects of i.t. SP, morphine or C-fiber CS. It is concluded that the N-terminal portion of GAL-(1–29) is critical for the biological activity of the intact peptide in the dorsal horn of the rat spinal cord. The similarity between the effects GAL-(1–16) and GAL-(1–29) indicates that they probably act on the same GAL receptor.

The effect of intrathecal galanin on the flexor reflex in rat: Increased depression after sciatic nerve section

The effect of intrathecal galanin (GAL) on the hamstring flexor reflex to sural nerve stimulation was compared in rats with intact and unilaterally sectioned sciatic nerves. GAL had a biphasic effect on the flexor reflex in rats with intact nerves, including facilitation, facilitation followed by depression and pure depression, in a dose-dependent manner. In axotomized rats, the depressive effect of GAL was significantly increased, occurring at lower drug concentrations. Furthermore, the degree of depression was significantly stronger with a more rapid onset after nerve section. It is concluded that along with an increase in GAL-like immunoreactivity in primary afferents, the inhibitory function of this neuropeptide is enhanced following axotomy. This functional change may be due to both pre- and postsynaptic mechanisms.