The use of opioids for the treatment of chronic non-cancer pain has become more widespread recently. Available data support the short-term use of opioids in clearly defined nociceptive and neuropathic pain states. Their use in 'pathological' pain states without a clear diagnosis, such as chronic low back pain, is more contentious. A decision to initiate opioid treatment in these conditions requires careful consideration of benefits and risks; the latter include not only commonly considered adverse effects such as constipation, but also opioid-induced hyperalgesia, abuse, addiction and diversion. Ideally, treatment goals should not only be relief of pain, but also improvement of function. Opioid treatment of chronic non-cancer pain requires informed consent by, and preferably a treatment contract with, the patient. Treatment should be initiated by a trial period with defined endpoints using slow-release or transdermal opioids. Ongoing management of the patient requires ideally a multi-disciplinary setting. Treatment should not be regarded as life-long and can be discontinued by tapering the dose.
Analgesics, Opioid ; adverse effects ; therapeutic use ; Humans ; Hyperalgesia ; chemically induced ; Low Back Pain ; drug therapy ; Pain, Intractable ; drug therapy ; Substance-Related Disorders ; prevention & control

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β adrenergic signaling in DRGs.
Adrenergic Agents ; pharmacology ; Animals ; Ganglia, Spinal ; drug effects ; Hyperalgesia ; drug therapy ; physiopathology ; Hypersensitivity ; drug therapy ; Male ; Maternal Deprivation ; Neurons ; drug effects ; Patch-Clamp Techniques ; methods ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Stress, Physiological ; physiology ; Visceral Pain ; chemically induced ; metabolism

Dexmedetomidine, which is a selective alpha2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 microg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 +/- 0.4, 9.1 +/- 1.9, 13.0 +/- 3.6, 16.6 +/- 2.4, and 24.4 +/- 1.6 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 +/- 4.2, 57.1 +/- 6.8, 34.3 +/- 5.7, 20.0 +/- 6.2, and 14.3 +/- 9.5 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).
Analgesics/*therapeutic use ; Animals ; Behavior, Animal/drug effects ; Dexmedetomidine/*therapeutic use ; Disease Models, Animal ; Hyperalgesia/chemically induced/*drug therapy ; Injections, Intraperitoneal ; Male ; Pain Threshold ; Rats ; Rats, Sprague-Dawley ; Vincristine/toxicity

Dexmedetomidine, which is a selective alpha2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 microg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 +/- 0.4, 9.1 +/- 1.9, 13.0 +/- 3.6, 16.6 +/- 2.4, and 24.4 +/- 1.6 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 +/- 4.2, 57.1 +/- 6.8, 34.3 +/- 5.7, 20.0 +/- 6.2, and 14.3 +/- 9.5 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).
Analgesics/*therapeutic use ; Animals ; Behavior, Animal/drug effects ; Dexmedetomidine/*therapeutic use ; Disease Models, Animal ; Hyperalgesia/chemically induced/*drug therapy ; Injections, Intraperitoneal ; Male ; Pain Threshold ; Rats ; Rats, Sprague-Dawley ; Vincristine/toxicity

PURPOSE: The aim of this study was to investigate the effect of epidural dexamethasone on analgesia and cytosolic phospholipase A2 (cPLA2) expression in the spinal cord in a rat formalin test. MATERIALS AND METHODS: Epidural dexamethasone injection was performed to Sprague-Dawley rats with a 25 gauge needle under fluoroscopy. Following the epidural injection, a formalin induced pain behavior test was performed. Next, the spinal cords corresponding to L4 dorsal root ganglion was extracted to observe the cPLA2 expression. RESULTS: There were no differences in pain response during phase I among the groups. The phase II pain response in 300 microg of epidural dexamethasone group decreased as compared to control, 30 microg of epidural dexamethasone, 100 microg of epidural dexamethasone, and 300 microg of systemic dexamethasone groups. The expression of cPLA2 decreased in Rexed laminae I-II in 300 microg of the epidural dexamethasone group compared with the ones in the control group. CONCLUSION: Taken together, these results suggest that 300 microg of epidural dexamethasone has an attenuating effect on the peripheral inflammatory tissue injury induced hyperalgesia and this effect is mediated through the inhibition of intraspinal cPLA2 expression and the primary site of action is the laminae I-II of the spinal cord.
Animals ; Anti-Inflammatory Agents/*pharmacology ; Dexamethasone/*pharmacology ; Formaldehyde/*adverse effects ; Group IV Phospholipases A2/*metabolism ; Hyperalgesia/*drug therapy ; Injections, Epidural ; Male ; Pain/chemically induced/*metabolism ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*metabolism

5-hydroxytryptamine (5-HT) released in inflammatory tissues plays a pivotal role in pain hypersensitivity. However, it is not clear whether 5-HT2A receptors in the inflamed tissues mediate this effect. The present study investigated the contribution of 5-HT2A receptors in the periphery to chronic inflammatory pain. Complete Freund's adjuvant (CFA) was injected subcutaneously in the hindpaw of rats. The selective 5-HT2A receptor antagonist ketanserin was given in the inflamed site. Paw withdrawal latency responding to heat or mechanical stimuli was measured. Expression of neuropeptide Y (NPY) in the spinal dorsal horn and dorsal root ganglia (DRG) was assayed using immunohistochemistry technique. The results showed that ketanserin administered in the inflamed site inhibited thermal hyperalgesia in a dose-dependent manner (20, 40 and 80 µg) induced by the intraplantar injection of CFA. Ketanserin given once per day at a dose of 80 µg abolished heat hyperalgesia and also attenuated mechanical allodynia on the third day. CFA injection increased the expression of NPY in superficial laminae of the spinal cord, but not in the DRG. The local treatment of ketanserin completely inhibited CFA-induced increase in NPY expression in superficial laminae of the spinal cord. These results indicated that activation of 5-HT2A receptors in the inflamed tissues was involved in the pathogenesis of inflammatory pain and the blockade of 5-HT2A receptors in the periphery could relieve pain hypersensitivity and normalize the cellular disorder in the spinal dorsal horn associated with pathological pain. The present study suggests that the peripheral 5-HT2A receptors can be a promising target for pharmaceutical therapy to treat chronic inflammatory pain without central nervous system side effects.
Animals ; Freund's Adjuvant ; adverse effects ; Ganglia, Spinal ; metabolism ; Hot Temperature ; Hyperalgesia ; chemically induced ; drug therapy ; Inflammation ; drug therapy ; Ketanserin ; pharmacology ; Neuropeptide Y ; metabolism ; Pain ; drug therapy ; Pain Measurement ; Rats ; Receptor, Serotonin, 5-HT2A ; metabolism ; Serotonin ; Serotonin 5-HT2 Receptor Antagonists ; pharmacology ; Spinal Cord Dorsal Horn ; metabolism

To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.
Animals ; Bee Venoms ; administration & dosage ; Benzamides ; pharmacology ; Epigenesis, Genetic ; Histone Deacetylase 1 ; genetics ; metabolism ; Histone Deacetylase 2 ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Hot Temperature ; Hyperalgesia ; drug therapy ; Inflammation ; drug therapy ; Injections, Subcutaneous ; Nociception ; Pain ; chemically induced ; drug therapy ; Pain Measurement ; Pyridines ; pharmacology ; Pyrimidines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Up-Regulation

Glycine and gamma-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.
Animals ; Baclofen/*administration & dosage/pharmacology ; Drug Delivery Systems ; GABA Agonists/administration & dosage/pharmacology ; GABA Antagonists/administration & dosage/pharmacology ; Glycine/*administration & dosage/pharmacology ; Hot Temperature ; Hyperalgesia/chemically induced/*drug therapy ; Injections, Spinal ; Male ; Mice ; Mice, Inbred ICR ; Muscimol/*administration & dosage/pharmacology ; Pain Threshold ; Random Allocation ; Strychnine ; gamma-Aminobutyric Acid/metabolism

BACKGROUND/AIMS: Acidic saline injections produce mechanical hyperresponsiveness in male Sprague-Dawley rats. We investigated the effect of milnacipran in conjunction with tramadol on the pain threshold in an acidic saline animal model of pain. METHODS: The left gastrocnemius muscle of 20 male rats was injected with 100 microL of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Rats administered acidic saline injections were separated into four study subgroups. After determining the pre-drug pain threshold, rats were injected intraperitoneally with one of the following regimens; saline, milnacipran alone (60 mg/kg), milnacipran (40 mg/kg) plus tramadol (20 mg/kg), or milnacipran (40 mg/kg) plus tramadol (40 mg/kg). Paw withdrawal in response to pressure was measured at 30 min, 120 min, and 5 days after injection. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) by applying increasing pressure to the right or left hind paw until the rat withdrew the paw. RESULTS: A potent antihyperalgesic effect was observed when tramadol and milnacipran were used in combination (injected paw, p=0.001; contralateral paw, p=0.012). This finding was observed only at 30 min after the combination treatment. CONCLUSIONS: We observed potentiation of the antihyperalgesic effect when milnacipran and tramadol were administered in combination in an animal model of fibromyalgia. Further research is required to determine the efficacy of various combination treatments in fibromyalgia in humans.
Analgesics, Opioid/administration & dosage/*pharmacology ; Animals ; Antidepressive Agents/administration & dosage/*pharmacology ; Behavior, Animal/drug effects ; Cyclopropanes/administration & dosage/*pharmacology ; Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Fibromyalgia/chemically induced/complications/*prevention & control ; Hydrogen-Ion Concentration ; Hyperalgesia/etiology/*prevention & control ; Injections, Intraperitoneal ; Male ; Pain/etiology/*prevention & control ; Pain Measurement ; Pain Threshold/*drug effects ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride ; Time Factors ; Tramadol/administration & dosage/*pharmacology

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism