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Tolerance to morphine analgesia following repeated administration disturbs the continuation of opioid therapy for severe pain. Emerging evidence suggests that the development of morphine tolerance may be antagonized by painful stimuli. To clarify the detailed mechanisms of these phenomena, we examined the effects of several pain stimuli on morphine-induced tolerance. Subcutaneous (s.c.) injection of morphine (10 mg/kg) produced an analgesic effect, which was evaluated by tail-pinch test. Morphine-induced analgesia was diminished by repeated administration of morphine (10 mg/kg, s.c.) once a day for 5 days, demonstrating the development of tolerance. Morphine analgesic tolerance was suppressed by nerve injury-induced neuropathic pain and formalin- or carrageenan-induced inflammatory pain. Tolerance to serum corticosterone elevation by morphine (10 mg/kg), which was evaluated by fluorometric assay, was also suppressed by formalin-induced inflammatory pain. Moreover, morphine analgesia induced by intracerebroventricular (10 nmol) or intrathecal (5 nmol) injection was diminished by repeated administration of morphine s.c., and this was also suppressed by carrageenan-induced inflammatory pain. These results suggest that morphine tolerance is inhibited by several pain stimuli, including neuropathic and inflammatory pain, through central mechanisms.

Aims: Although a pharmacological relationship is known to exist between nicotine and morphine, the exact mechanisms are unclear. Here, we investigated crosstalk between the endogenous opioid system and nicotinic acetylcholine receptors (nAChRs), specifically in nicotine-induced analgesia and activation of the hypothalamic-pituitary-adrenal (HPA) axis., Main Methods: Nicotine and morphine were administered subcutaneously to mice and the effects of these drugs on analgesia and serum corticosterone (SCS) levels were evaluated by the tail-pinch method and fluorometric assay, respectively., Key Findings: Both nicotine and morphine produced analgesia and SCS increase after a single injection. Nicotine-induced analgesia was prevented by both mecamylamine (MEC; 1mg/kg) and naloxone (NLX; 1mg/kg), and also by repeated administration of morphine or nicotine. Morphine-induced analgesia was prevented by NLX, but not MEC, and by repeated administration of morphine, but not nicotine. Conversely, the nicotine-induced increase in SCS level was prevented by MEC, but not NLX. Morphine-induced SCS increase was prevented by NLX, but not MEC. Moreover, nicotine-induced analgesia was suppressed by dihydro-β-erythroidine (DHβE; an antagonist for the α4β2 nAChR) or methyllycaconitine (MLA; an antagonist for the α7 nAChR). The nicotine-induced increase in SCS level was suppressed by DHβE, but not MLA., Significance: Nicotine-induced analgesia may involve the endogenous opioid system through crosstalk with nicotinic pathways. However, the relationship between these systems does not extend to cooperative actions in nicotine-induced HPA-axis activation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Fibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS)., Results: In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief., Conclusions: These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factor belonging to a nuclear hormone receptor superfamily, containing three isoforms (alpha, beta/delta, and gamma). PPARs play a critical physiological role as a primary lipid sensor and regulator of lipid metabolism. Thus, its ligands are clinically used for treatment of type 2 diabetes and hyperlipidemia. On the other hand, PPAR ligands exert the antineuroinflammatory activity through preventing upregulation of inflammatory mediators in animal models for neurodegenerative disease and autoimmune disease. Neuropathic pain and inflammatory pain, clinically important one, are chronically progressed and underlain by neuroinflammation. In a few years, some studies using experimental models emerge that administration of PPAR ligands reduces inflammatory pain and neuropathic pain. PPAR ligands repress expression of genes for inflammatory mediators involved in both pains, such as proinflammatory cytokines, by a molecular mechanism termed ligand-dependent direct transrepression. Alternative mechanism is independent of transcriptional regulation of target genes, such as inhibition of activity of ion channels involved in the development of inflammatory pain and neuropathic pain, and therefore the analgesic effect occurs with rapid onset. The effects of PPAR ligands on neuroinflammation in animal models suggest their possible use for treating human inflammatory pain and neuropathic pain.

Elucidation of the mechanism of neuropathic pain caused by vincristine is required because long-term treatment with this anticancer agent often causes neuropathic pain. We refer to the involvement of inflammatory mediators in vincristine-induced neuropathic pain in this review. Several reports using rodents have shown that long-lasting neuropathic pain (mechanical allodynia) is caused by repeated systemic injection of vincristine. Vincristine damaged Schwann cells and DRG neurons in this model. Vincristine-induced macrophage infiltration in the peripheral nervous system (PNS) and macrophage-derived IL-6 elicited mechanical allodynia. These findings proved that inhibition of IL-6 function prevented neuropathic pain caused by vincristine. In the central nervous system (CNS), activation of microglia and astrocytes in the spinal cord were demonstrated after long-term vincristine treatment. TNF-alpha was upregulated in activated microglia and astrocytes, and inhibition of TNF-alpha function attenuated neuropathic pain caused by vincristine. These results suggest that vincristine induces macrophage infiltration to the damaged PNS, and that macrophage-derived inflammatory cytokines such as IL-6 elicits neuroinflammation. Signal transduction of pain from the PNS to the CNS activates microglia and astrocytes, and these activated glial cells release inflammatory cytokines such as TNF-alpha. In the CNS, these inflammatory cytokines have an important role in the neuropathic pain caused by vincristine. Immune-modulating agents that prevent activation of immune cells and/or the inhibitory agents of inflammatory cytokines could prevent the neuropathic pain caused by vincristine. These agents could increase the tolerability of vincristine when used for the treatment of leukemia and lymphoma.

Although the clinical use of vincristine is limited by its adverse effect, neuropathic pain, the mechanism of this effect is poorly understood. Recently, reports demonstrated that inflammatory and immune responses play an important role in the neuropathic pain that follows peripheral nerve injury. In this study, we examined the role of macrophage-derived interleukin (IL)-6 in vincristine-induced mechanical allodynia. Vincristine sulfate (0.01-0.1 mg/kg, i.p.) was administered to male ICR mice and BALB/c mice once per day for 7 or 14 days. Mechanical allodynia was evaluated by withdrawal responses, using von Frey filaments from day 0 to day 28. In both ICR mice and BALB/c mice, significant dose-dependent increases in the percentage of withdrawal responses were observed from day 3 to day 28 following repeated administration of vincristine (0.1 mg/kg). As determined by immunohistochemistry, the number of macrophages in the region of the sciatic nerve and lumbar dorsal root ganglion was significantly increased on day 7 of vincristine administration. The expression of IL-6 was increased by vincristine administration and was co-localized in the invading macrophage. Moreover, a neutralizing antibody of IL-6, which was injected into areas surrounding the sciatic nerve on day 0, 3, and 6, significantly attenuated vincristine-induced mechanical allodynia from day 7 to day 28. In addition, the incidence of vincristine-induced mechanical allodynia in IL-6 knockout mice was lower than that in wild type mice from day 3 to day 28. These results suggest that the invading peripheral macrophage-derived IL-6 plays a critical role in vincristine-induced mechanical allodynia.

Nicotine is neuronal stimulating drug in the central nervous system and elicits various effects through nicotinic acetylcholine receptors. As previously reported, nicotine has an antinociceptive effect through activation of endogenous opioid neurons. However, detailed mechanisms of nicotine-induced antinociception are uncertain. In this study, we focused on spinal cord and investigated the involvement of endogenous opioidergic neurons in nicotine-induced antinociception in mice. In the tail-pinch test, subcutaneously administered nicotine (5 mg/kg) produced maximal antinociception 0.5 h after nicotine administration; this was attenuated by mecamylamine (MEC, 3 mg/kg, s.c.) or naloxone (NLX, 1 mg/kg, s.c.) administration. Intrathecal nicotine (10 mug) produced maximal antinociception at 2 min and this was also attenuated by MEC (3 mg/kg, s.c.) or NLX (1 mg/kg, s.c.) administration. The preproenkephalin (ppENK) mRNA level in spinal cord, but not dorsal root ganglion, was significantly increased 2 h following nicotine administration and recovered to control level 4 h after nicotine (5 mg/kg, s.c.) administration. This increase in ppENK mRNA level was inhibited by MEC (3 mg/kg, s.c.). The mRNA levels of preprodynorphin and preproopiomelanocortin were not increased by nicotine (5 mg/kg, s.c.). In the dorsal horn of the lumbar spinal cord, methionine-enkephalin (Met-ENK)-like IR was remarkably reduced at 0.5 h following nicotine administration and recovered to control levels by 2 h after nicotine (3 mg/kg, s.c.) administration. These results suggest that nicotine has an antinociceptive effect by promoting the release of Met-ENK, but not dynorphins and endorphins, from activated opioidergic neurons in spinal cord.

Although the serine/threonine protein kinases involved in the pharmacological action of morphine are well recognized, the critical contribution of serine/threonine protein phosphatase (PP) has been appreciated on to a slight degree. We examined the involvement of subtypes of serine/threonine protein phosphatase (PP) in the antinociceptive effect of morphine in mice. The antinociceptive effect of subcutaneously administered morphine was attenuated by simultaneously intracerebroventricular (i.c.v.) or intrathecal (i.t.) injection of okadaic acid (OA), a PP inhibitor. To reveal which subtypes of PPs participated in the antinociceptive effect of morphine, mice received i.c.v. or i.t. injections of antisense oligodeoxynucleotide (AS-ODN) directed against either the PP 2 A or PP5 subtypes of PPs before assessment of morphine-induced antinociception. Pretreatment with AS-ODN against PP 2 A or PP5 via each route weakened the antinociceptive effect of morphine, accompanied by reduction of expression levels of PP in the periaqueductal gray (PAG) and the spinal cord. Subcutaneously administered morphine increased activity of OA-sensitive PPs in the PAG and the spinal cord in a dose-dependent manner; this was prevented by concurrent administration of naloxone. These results suggest that PP 2 A and PP5 are involved in the antinociceptive effect of morphine in mice.

Recently we developed a new technique, known as peripheral nociception test or algogenic-induced nociceptive flexion (ANF) test, to study the in vivo signal transduction of pain at the peripheral nerve endings in mice. In the present report, we examined the sensitivity of the method to detect pain signal and the stresses induced by the test on experimental animals. In the algogenic-induced biting and licking (ABL) test, bradykinin could not induce significant biting-licking response even at a dose of 1nmol. It induced significant biting-licking response only at 10nmol. However, with the ANF test, 100fmol of bradykinin was enough to produce sharp and significant nociceptive flexion response. Similarly, substance P, ATP and ONO-54918-07, a stable prostaglandin I(2) agonist, induced nociceptive flexion response in ANF test at much lower doses than needed to induce biting-licking responses in ABL test. Next, we measured the plasma corticosterone level after different nociception tests, which is a measure of stress on animals due to experimental manipulations. However, no significant rise in corticosterone level was observed with ANF test. Altogether, these findings indicate that the ANF test is a highly sensitive and less stressful technique to study in vivo mechanisms of pain at the peripheral nerve ending.

Morphine antinociception after various administration routes was estimated by the tail-flick method in rats. The antinociceptive ED50 (AD50) values for i.c.v., i.t., i.c.v. + i.t. (4:1 dose ratio) and s.c. were 6.9 micrograms, 0.49 + 0.12 micrograms and 2.7 mg/kg, respectively. Isobolographic analysis of AD50 (except s.c.) suggested that concurrent administration of i.c.v. and i.t. morphine interacted multiplicatively to produce antinociception. Morphine content in the CNS after administration of AD50 morphine for each route was estimated. Isobolographic analysis of morphine content revealed that supraspinal and spinal morphine interacted multiplicatively to produce antinociception after i.c.v. + i.t. and s.c. administration. Comparison of the dose-response curves (i.c.v. alone, i.t. alone, various i.c.v. + fixed i.t., fixed i.c.v. + various i.t.) suggested that supraspinal and spinal morphine can potentiate the antinociception induced by the other site, and that they have almost equal importance in the antinociceptive synergism. These results provide direct evidence for the synergism between supraspinal and spinal morphine to play an important role in the antinociception of systemically administered morphine.

The development of tolerance to and dependence on morphine over 1-8 days treatment with morphine were studied with time in rats in which the nucleus reticularis gigantocellularis (NRGC), including the nucleus reticularis paragigantocellularis, were electrically destructed. The NRGC of SD male rats was bilaterally lesioned (DC, 0.5 mA, 40 sec), and morphine analgesia was estimated by the tail flick method. Morphine analgesia in NRGC-destructed rats (D-rat) was reduced to about 50% of that in sham-operated rats (S-rat). The dose of morphine to produce equi-analgesia increased 2-21.8 times during 1-8 days treatment with morphine in S-rat. Throughout this period, ratios of the equi-analgesic dose in D-rat to that in S-rat were almost the same, i.e., the rate of tolerance development to morphine analgesia in D-rat was to the same degree as that in S-rat. Administration of naloxone after 1-6 days treatment with morphine elicited body weight loss and increase in plasma corticosterone (Pcs), degrees of which were dependent on the dose of naloxone or the period of morphine treatment. No difference in these abstinence signs were detected between S- and D-rat, i.e., the rate of development of dependence on morphine in D-rat was to the same degree as that in S-rat. These results suggest that the NRGC participates in the development of morphine analgesia, but does not participate in the development of tolerance to and dependence on morphine.

Effects of electroacupuncture (EA) on pain threshold and beta-endorphin (beta-End) contents in plasma, pituitary (Pit), hypothalamus (Hyp) and cerebrospinal fluid (CSF) were studied in nontreated, dexamethasone (Dex) treated and adrenalectomized (Adrex) male SD rats by the use of specific determination of rat beta-End (combination of HPLC and RIA). EA increased pain threshold and plasma beta-End with no effect on beta-End contents in Pit, Hyp and CSF. Dex did not affect control pain threshold, but tended to reduce EA-induced increase in pain threshold (EA-analgesia, EAA) and EA-induced increase in plasma beta-End. Adrex increased plasma beta-End without change in control pain threshold. Adrex tended to reduce EAA, but a tendency of further increase in plasma beta-End was observed after addition of EA. Adrex increased Pit beta-End, but no further change in Pit beta-End was observed after addition of EA. A positive correlation between plasma beta-End and plasma ACTH was observed in nontreated, Dex treated and Adrex rats. No correlation between plasma beta-End and potency of EAA was observed in nontreated, Dex treated and Adrex rats. The hind-paw pressure test without EA increased plasma beta-End to the same degree as that produced by EA, and it produced no analgesia. These results suggest that Pit beta-End may not be mainly involved in the development of EAA.

Background Neuropathic pain is caused by neural damage or dysfunction and neuropathic pain-related symptoms are resistant to conventional analgesics. Neuroinflammation due to the cytokine-chemokine network may play a pivotal role in neuropathic pain. We demonstrate that macrophage inflammatory protein-1β ( MIP-1β) participates in neuropathic pain. Methods Mice received partial sciatic nerve ligation ( PSL), and tactile allodynia and thermal hyperalgesia were assessed by von Frey test and Hargreaves test, respectively. Agents were administered into the region surrounding the sciatic nerve ( SCN). Results Using reverse transcription polymerase chain reaction, the m RNA expressions of MIP-1β and its receptor ( CC-chemokine receptor 5; CCR5) in the injured SCN were up-regulated after PSL. MIP-1β immunoreactivity was localized in macrophages and Schwann cells and increased in the injured SCN on day 1. PSL-induced tactile allodynia on days 4 to 7 was prevented by the administration of MIP-1β neutralizing antibody (anti- MIP-1β; on days 0, 3 and 6). PSL-induced up-regulations of inflammatory cytokine-chemokine m RNAs in the injured SCN were suppressed with anti- MIP-1β treatment on day 7. Administration of CCR5 antagonist, D-ala-peptide T-amide (on days 0, 3 and 6) prevented tactile allodynia and thermal hyperalgesia on days 4 to 14. Single administration of recombinant mouse MIP-1β (rm MIP-1β) elicited tactile allodynia. Moreover, rm MIP-1β increased the m RNA expression of inflammatory mediators in the SCN on day 1 after administration. Conclusions These results suggest that MIP-1β is a novel key mediator, and the peripheral MIP-1β- CCR5 axis contributes to neuropathic pain. Therefore, investigation of this cascade might be a validated approach for the elucidation of neuropathic pain mechanisms. [ABSTRACT FROM AUTHOR]