The opposing effects of interleukin-1 β microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats

doi:10.1016/0006-8993(95)00980-5

Brain Research

Volume 700, Issues 1–2, 27 November 1995, Pages 271-278

https://doi.org/10.1016/0006-8993(95)00980-5 Get rights and content

Abstract

The effects of microinjections of recombinant human interleukin-1β (rhIL-1β) into the hypothalamus and neighboring basal forebrain on nociceptive behavior were studied using a hot-plate test in rats. The microinjection of rhIL-1β at doses between 5 pg/kg and 50 pg/kg into the medial part of the preoptic area (MPO) reduced the paw-withdrawal latency. The maximal reduction was obtained 30 min after the injection of rhIL-1β at 20 pg/kg. RhIL-1β (20 pg/kg)-induced hyperalgesia was completely blocked by the simultaneous injection of IL-1 receptor antagonist (IL-1ra, 20 ng/kg), Na salicylate (200 ng/kg) or α-melanocyte-stimulating hormone (α-MSH, 20 ng/kg). The intra-MPO injection of rhIL-1β at doses of less than 5 pg/kg or more than 50 pg/kg (up to 2 ng/kg) had no effect on nociceptive behavior. The microinjection of rhIL-1β (20 pg/kg) into the lateral part of the preoptic area, the median preoptic nucleus and the diagonal band of Broca also reduced the latency. On the other hand, the microinjection of rhIL-1β (20 pg/kg) into the paraventricular nucleus, the lateral hypothalamic area and the septal nucleus had no effect on nociception. The microinjection of rhIL-1β (20 pg/kg–50 pg/kg) into the ventromedial hypothalamus produced a prolongation of the paw-withdrawal latency. A maximal prolongation was obtained 10 min after the injection of rhIL-1β at 50 pg/kg. This reaction was also blocked by the simultaneous injection of IL-1ra (50 ng/kg) and Na salicylate (500 ng/kg). These findings indicate that IL-1β in the MPO and the VMH produces hyperalgesia and analgesia, respectively, while, in addition, both effects are mediated by IL-1 receptors and the synthesis of prostaglandins.

Reference (36)

AbbottF.V. et al.
Analgesia produced by stimulation of limbic structures and its related epileptiform after-discharges
Exp. Neurol.
(1978)
FukuokaH. et al.
Cutaneous hyperalgesia induced by peripheral injection of interleukin-1β in the rat
Brain Res.
(1994)
HigginsG.A. et al.
Induction of interleukin-1β mRNA in adult rat brain
Mol. Brain Res.
(1991)
HoriT. et al.
Immune cytokines and regulation of body temperature, food intake and cellular immunity
Brain Res. Bull.
(1991)
HoriT. et al.
Effects of interleukin-1 and arachidonate on the preoptic and anterior hypothalamic neurons
Brain Res. Bull.
(1988)
KatsuuraG. et al.
Identification of a high-affinity receptor for interleukin-1 beta in rat brain
Biochem. Biophys. Res. Commun.
(1988)
KuriyamaK. et al.
Actions of interferon α and interleukin-1β on the glucose-responsive neurons in the ventromedial hypothalamus
Brain Res. Bull.
(1990)
MinamiM. et al.
Immobilization stress induces interleukin-1β mRNA in the rat hypothalamus
Neurosci. Lett.
(1991)
NakashimaT. et al.
Recombinant human interleukin-1β alters the activity of preoptic thermosensitive neurons in vitro
Brain Res. Bull.
(1989)
OkaT. et al.
Intracerebroventricular injection of interleukin-1β induces hyperalgesia in rats
Brain Res.
(1993)

OkaT. et al.

Intracerebroventricular injection of interleukin-1β enhances nociceptive neuronal responses of trigeminal nucleus caudalis in rats

Brain Res.

(1994)

OkaT. et al.

Intracerebroventricular injection of prostaglandin E₂ induces thermal hyperalgesia in rats: the possible involvement of EP₃ receptors

Brain Res.

(1994)

Plata-SalamánC.R. et al.

Tumor necrosis factor and interleukin-1β: suppression of food intake by direct action in the central nervous system

Brain Res.

(1988)

RhodesD.L. et al.

Analgesia from rostral brain stem stimulation in the rat

Brain Res.

(1978)

TakeshigeC. et al.

Descending pain inhibitory system involved in acupuncture analgesia

Brain Res. Bull.

(1992)

TatroJ.B.

Melanotropin receptors in the brain are differentially distributed and recognized both corticotropin and α-melanocyte stimulating hormone

Brain Res.

(1990)

VidalC. et al.

The effect of medial hypothalamus lesions on pain control

Brain Res.

(1980)

XinL. et al.

Blockade by interleukin-1 receptor antagonist of Il-1β-induced neuronal activity in guinea pig preoptic area slices

Brain Res.

(1992)

Cited by (48)

The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla
2013, Neuroscience
While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK₂ receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.
Chronic blockade of interleukin-1 (IL-1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury
2011, European Journal of Pain
Citation Excerpt :
A growing body of evidence indicates that the pro-inflammatory cytokine interleukin-1 (IL-1) is involved in pain sensation (Watkins and Maier, 2002; Wolf et al., 2003; Shavit et al., 2005; Bessler et al., 2006; Guimaraes et al., 2006), as well as in neuropathic pain (Raghavendra et al., 2002; DeLeo et al., 2004; Wolf et al., 2006; Honore et al., 2006; Ledeboer et al., 2007; McGaraughty et al., 2007; Norman et al., 2009). Numerous reports have shown that peripheral, spinal, or cerebral administration of IL-1β usually produces hyperalgesia and allodynia (Ferreira et al., 1988; Oka et al., 1993; Watkins et al., 1994; Oka et al., 1995; Safieh-Garabedian et al., 1995; Tadano et al., 1999; Reeve et al., 2000; Falchi et al., 2001; Lee et al., 2004), whereas its blockade at the spinal level prevents hyperalgesia induced by various immune challenges (Watkins et al., 1994, 1997; Milligan et al., 2001; Samad et al., 2001). IL-1 may be particularly relevant to neuropathic pain, as peripheral nerve injury triggers an inflammatory response (Rotshenker et al., 1992; DeLeo et al., 1997; Shamash et al., 2002), including activation of spinal cord glia and the secretion of pro-inflammatory cytokines (Clatworthy et al., 1995; Colburn et al., 1999; Raghavendra et al., 2003a,b; DeLeo et al., 2004).
Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL-1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle-treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1 ± 1.1% of the axons); whereas IL-1ra-treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8 ± 0.4% of the axons). To test whether IL-1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL-1ra four days following SNT, after the allodynic response was already manifested. Whereas saline-treated mice displayed robust allodynia, acute IL-1ra treatment induced long-lasting attenuation of the allodynic response. The results support our hypothesis that IL-1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.
Interleukin-1 signaling is required for induction and maintenance of postoperative incisional pain: Genetic and pharmacological studies in mice
2008, Brain, Behavior, and Immunity
Postoperative incisional pain is characterized by persistent acute pain in the area of the cut, and is associated with release of proinflammatory cytokines, including interleukin-1 (IL-1), which play important hyperalgesic and allodynic roles in various inflammatory conditions. In the present study, we tested the role of IL-1 signaling in postoperative incisional pain using three mouse strains impaired in IL-1 signaling due to deletion of the IL-1 type I receptor on a mixed genetic background (IL-1rKO) or congenic background (IL-1rKOCog), or due to transgenic over-expression of IL-1 receptor antagonist (IL-1raTG). We used the relevant wild-type (WT) mice both as controls for the mutant strains, and for assessing the effects of pharmacological blockade of IL-1-signaling. Mechanosensitivity was assessed using the von-Frey filament test before, and up to 4 days following plantar incision, an animal model of postoperative pain. WT mice developed significant allodynia in the incised, compared with the intact, hind-paw beginning 3 h after the incision and lasting up to 48 h postoperatively. In contrast, IL-1rKO, IL-1rKOCog, and IL-1raTG mice, as well as WT mice chronically treated with IL-1ra, did not display increased mechanical pain sensitivity in either hind-paw. To test the hypothesis that IL-1-signaling is also involved in the maintenance of postoperative pain, WT mice were acutely treated with IL-1ra 24 h following the incision, when allodynia was already evident. This treatment reversed the allodynic response throughout the observation period. Together, these findings suggest that IL-1 plays a critical role in the development and maintenance of postoperative incisional pain.
Interleukin-1 signaling modulates stress-induced analgesia
2007, Brain, Behavior, and Immunity
Citation Excerpt :
The span of this analgesic response is similar to the SIA found in the present study, which is also short-lived. That IL-1 had no effect on pain sensitivity when administered directly into the paraventricular nucleus (PVN) of the hypothalamus (Oka et al., 1995), suggests that SIA is mediated by a separate mechanism than HPA axis activation. Consistent with these data, i.c.v administration of corticotropin-releasing hormone (CRH) shown to induce many stress-like behaviors, such as increased startle response (Cole and Koob, 1988) and decreased sleeping time (Sherman and Kalin, 1987), but had no effect on pain threshold (Sherman and Kalin, 1987).
Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed “stress-induced analgesia” (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2 min swim stress at one of three water temperatures: 32 °C (mild stress), 20–23 °C (moderate stress), or 15 °C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.
Role of substantia innominata in cerebral blood flow autoregulation
2007, Brain Research
Ascending projections from the substantia innominata (SI) may have an important role in the regulation of cerebral blood flow (CBF). However, several reports have suggested that unilateral lesion of the SI does not affect CBF autoregulation. On the other hand, it is also reported that several cortical and subcortical functions may be regulated not only by ipsilateral SI, but also by contralateral SI. Thus, the objective of this study is to test the hypothesis that bilateral lesions of the SI affect CBF autoregulation. Experiments were performed on anesthetized male Sprague–Dawley rats. Ibotenic acid or physiological saline was microinjected into bilateral SI. Rats were classified into four groups as follows: bilateral SI lesion rats (ibotenic acid was injected bilaterally), left or right SI lesion rats (ibotenic acid was injected into the unilateral SI and saline into the contralateral SI), and control rats (saline was injected bilaterally). Ten days after injection, CBF in the left frontal cortex was measured by laser-Doppler flowmetry during stepwise controlled hemorrhagic hypotension. In bilateral SI lesion rats, CBF was started to decrease significantly at 80 mm Hg (p < 0.01). In the other three groups, CBF was well maintained until 50 mm Hg. Changes in CBF through stepwise hypotension in bilateral SI lesion rats were significantly different from the other groups (p < 0.01). These results suggest that bilateral SI regulates cortical vasodilator mechanisms during hemorrhagic hypotension. Under unilateral SI lesion, some compensatory effects from the contralateral SI may maintain CBF autoregulation.
The differential role of prostaglandin E<inf>2</inf> receptors in the CNS response to systemic immune challenge
2007, Psychoneuroimmunology, Two-Volume Set

View all citing articles on Scopus

View full text

The opposing effects of interleukin-1 β microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats

Abstract

Exp. Neurol.

Brain Res.

Mol. Brain Res.

Brain Res. Bull.

Brain Res. Bull.

Biochem. Biophys. Res. Commun.

Brain Res. Bull.

Neurosci. Lett.

Brain Res. Bull.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res. Bull.

Brain Res.

Brain Res.

Brain Res.