Abstract
Opioids are standard therapy for the treatment of pain; however, adverse effects limit
their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia,
but their effect on opioid-induced side effects is little known. Thus, the goal of
this study was to evaluate the action of the peptide Phα1β, a voltage-gated calcium
channel blocker, on the antinociceptive and adverse effects produced by morphine in
mice. A single administration of morphine (3–10 mg/kg) was able to reduce heat nociception
as well as decrease gastrointestinal transit. The antinociception caused by a single
injection of morphine was slightly increased by an intrathecal injection of Phα1β
(30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal
syndrome, and constipation, and the Phα1β (.1–30 pmol/site, intrathecal) was able
to reverse these effects. Finally, the effects produced by the native form of Phα1β
were fully mimicked by a recombinant version of this peptide. Taken together, these
data show that Phα1β was effective in potentiating the analgesia caused by a single
dose of morphine as well as in reducing tolerance and the adverse effects induced
by repeated administration of morphine, indicating its potential use as an adjuvant
drug in combination with opioids.
Perspective
This article presents preclinical evidence for a useful adjuvant drug in opioid treatment.
Phα1β, a peptide calcium channel blocker, could be used not only to potentiate morphine
analgesia but also to reduce the adverse effects caused by repeated administration
of morphine.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Pharmacological analysis of paregoric elixir and its constituents: In vitro and in vivo studies.J Ethnopharmacol. 2007; 114: 218-226
- Opioid-induced hyperalgesia: A qualitative systematic review.Anesthesiology. 2006; 104: 570-587
- Cardiovascular effects of omega-conopeptides in conscious rats: Mechanisms of action.J Cardiovasc Pharmacol. 1992; 20: 756-764
- Structure and regulation of voltage-gated Ca2+ channels.Annu Rev Cell Dev Biol. 2000; 16: 521-555
- Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian “armed” spider Phoneutria nigriventer (Keys).Toxicon. 1993; 31: 35-42
- Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain.Pain. 2011; 152: 2224-2232
- Efficient analysis of experimental observations.Annu Rev Pharmacol Toxicol. 1980; 20: 441-462
- Spinal L-type calcium channel blockade abolishes opioid-induced sensory hypersensitivity and antinociceptive tolerance.Anesth Analg. 2005; 101: 1730-1735
- Presynaptic Ca2+ channels—Integration centers for neuronal signaling pathways.Trends Neurosci. 2006; 29: 617-624
- Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.Nat Neurosci. 2013; 16: 183-192
- Chronic morphine treatment and withdrawal increase extracellular levels of norepinephrine in the rat bed nucleus of the stria terminalis.J Neurochem. 2000; 75: 741-748
- Spinally delivered N-, P/Q- and L-type Ca2+-channel blockers potentiate morphine analgesia in mice.Life Sci. 2003; 73: 2873-2881
- Antinociceptive and adverse effects of mu- and kappa-opioid receptor agonists: A comparison of morphine and U50488-H.Basic Clin Pharmacol Toxicol. 2008; 103: 419-427
- Calcium channel antagonist peptides define several components of transmitter release in the hippocampus.Neuropharmacology. 1994; 33: 1211-1219
- Phoneutria nigriventer venom: A cocktail of toxins that affect ion channels.Cell Mol Neurobiol. 2002; 22: 579-588
- Methylnaltrexone in the treatment of opioid-induced constipation.Clin Exp Gastroenterol. 2008; 1: 49-58
- Intrathecal morphine in mice: A new technique.Eur J Pharmacol. 1980; 67: 313-316
- Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia.Neurosci Res. 2000; 38: 113-116
- Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids.Eur J Pain. 2012; 16: 690-705
- Neural substrates of opiate withdrawal.Trends Neurosci. 1992; 15: 186-191
- Molecular mechanisms and regulation of opioid receptor signaling.Annu Rev Pharmacol Toxicol. 2000; 40: 389-430
- A comprehensive review of opioid-induced hyperalgesia.Pain Physician. 2011; 14: 145-161
- Hyperalgesia during opioid abstinence: Mediation by glutamate and substance P.Anesth Analg. 2002; 95: 979-984
- Opioid-induced hyperalgesia: A review of epidemiology, mechanisms and management.Singapore Med J. 2012; 53: 357-360
- Quantitative method for assessing one symptom of the withdrawal syndrome in mice after chronic morphine administration.Nature. 1971; 234: 223-224
- Ziconotide: A review of its pharmacology and use in the treatment of pain.Neuropsychiatr Dis Treat. 2007; 3: 69-85
- Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence.Eur J Pharmacol. 2008; 586: 130-138
- Habituation to sham testing procedures modifies tail-flick latencies: Effects on nociception rather than vasomotor tone.Pain. 1989; 39: 103-107
- Mechanisms that underlie μ-opioid receptor agonist-induced constipation; differential involvement of μ-opioid receptor sites and responsible regions.J Pharmacol Exp Ther. 2013; 347: 91-99
- Bioavailability of ziconotide in brain: Influx from blood, stability, and diffusion.Peptides. 2000; 21: 491-501
- Spinal antinociceptive action of an N-type voltage-dependent calcium channel blocker and the synergistic interaction with morphine.Anesthesiology. 1996; 84: 636-643
- Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse.J Pharmacol Exp Ther. 1984; 230: 341-348
- Spider peptide Phα1β induces analgesic effect in a model of cancer pain.Cancer Sci. 2013; 104: 1226-1230
- Spinal cord mechanisms of opioid tolerance and dependence: Fos-like immunoreactivity increases in subpopulations of spinal cord neurons during withdrawal.Neuroscience. 1996; 72: 233-242
- Extrinsic control of digestive tract motility.in: Johnson L.R. Physiology of the Gastrointestinal Tract. Raven Press, New York1981: 289-333
- Is withdrawal hyperalgesia in morphine-dependent mice a direct effect of a low concentration of the residual drug?.Addict Biol. 2009; 14: 438-446
- Mu-opioid receptor activation reduces multiple components of high-threshold calcium current in rat sensory neurons.J Neurosci. 1995; 15: 4315-4327
- Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.Cell. 2009; 137: 1148-1159
- Peptide opioid antagonist separates peripheral and central opioid antitransit effects.J Pharmacol Exp Ther. 1987; 243: 492-500
- Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom.Pain. 2008; 140: 115-126
- Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: A randomized controlled trial.JAMA. 2004; 291: 63-70
- Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.Eur J Pharm Sci. 2003; 20: 357-363
- Differential expression of L- and N-type voltage-sensitive calcium channels in the spinal cord of morphine+nimodipine treated rats.Brain Res. 2009; 1249: 128-134
- Inhibition of high voltage activated calcium channels by spider toxin PnTx3-6.J Pharmacol Exp Ther. 2005; 314: 1370-1377
- Intrathecal ziconotide in the treatment of chronic nonmalignant pain: A randomized, double-blind, placebo-controlled clinical trial.Neuromodulation. 2006; 9: 75-86
- Analgesic properties of ziconotide, a selective blocker of N-type neuronal calcium channels.CNS Drug Rev. 2000; 6: 1-20
- Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent.Eur J Pharmacol. 2010; 636: 73-81
- Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine tolerance.Eur J Neurosci. 2004; 20: 3516-3519
- Ethical guidelines for investigations of experimental pain in conscious animals.Pain. 1983; 16: 109-110
Article info
Publication history
Published online: March 11, 2014
Accepted:
February 27,
2014
Received in revised form:
February 21,
2014
Received:
December 14,
2013
Footnotes
This study was supported by the Instituto do Milenio MCT/CNPq, Instituto Nacional de Ciência e Tecnologia em Medicina Molecular MCT/CNPq, CAPES, AUX-PE Toxinologia, PRONEX, and FAPEMIG.
The authors have no conflicts of interest to disclose.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
Identification
Copyright
© 2014 Published by Elsevier Inc.
