Abstract
Cancer patients often suffer from pain and most will be prescribed μ-opioids. μ-opioids
are not satisfactory in treating cancer pain and are associated with multiple debilitating
side effects. Recent studies show that μ and δ opioid receptors are separately expressed
on IB4 (−) and IB4 (+) neurons, which control thermal and mechanical pain, respectively.
In this study we investigated IB4 (+) and IB4 (−) neurons in mechanical and thermal
hypersensitivity in an orthotopic mouse oral cancer model. We used a δ opioid receptor
agonist and a P2X3 antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a
key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia.
Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced
mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally
administered pharmacological agents targeting IB4 (+) neurons, such as a selective
δ-opioid receptor agonist or P2X3 antagonist, might be useful in treating oral cancer pain.
Perspective
To clarify the mechanisms of oral cancer pain, we examined the differential role of
IB4 (+) and IB4 (−) neurons. Characterization of these 2 subsets of putative nociceptors
is important for further development of effective clinical cancer pain relief.
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
- Nerve growth factor is a potential therapeutic target in breast cancer.Cancer Res. 2008; 68: 346-351
- The skin as a neurotrophic organ.Neuroscientist. 2007; 13: 371-382
- Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors.J Neurosci. 2006; 26: 2981-2990
- Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat.Eur J Neurosci. 1998; 10: 1282-1291
- A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury.J Neurosci. 1998; 18: 3059-3072
- Nerve growth factor evokes hyperalgesia in mice lacking the low-affinity neurotrophin receptor p75.Neurosci Lett. 1998; 255: 87-90
- GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican.Eur J Neurosci. 2008; 28: 12-19
- The expression of P2X3 purinoreceptors in sensory neurons: Effects of axotomy and glial-derived neurotrophic factor.Mol Cell Neurosci. 1998; 12: 256-268
- Cancer-related bone pain is attenuated by a systemically available delta-opioid receptor agonist.Pain. 2006; 122: 174-181
- Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse.Pain. 2005; 115: 37-49
- Opioids in cancer and chronic non-cancer pain therapy – indications and controversies.Acta Anaesthesiol Scand. 2001; 45: 1059-1066
- Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli.Proc Natl Acad Sci U S A. 2009; 106: 9075-9080
- Opioid-induced stimulation of fetal respiratory activity by [D-Ala2]deltorphin I.Eur J Pharmacol. 1993; 230: 85-88
- Cancer pain and analgesia.Ann N Y Acad Sci. 2008; 1138: 278-298
- JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence.J Pharmacol Exp Ther. 2009; 329: 241-251
- Evaluation of pain in patients with oral squamous cell carcinoma.J Pain. 2004; 5: 505-510
- Direct dependence studies in rats with agents selective for different types of opioid receptor.J Pharmacol Exp Ther. 1988; 246: 950-955
- Differential response properties of IB(4)-positive and -negative unmyelinated sensory neurons to protons and capsaicin.J Neurophysiol. 2003; 89: 513-524
- Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans.Neurology. 1997; 48: 501-505
- Orofacial pain in cancer: Part II–clinical perspectives and management.J Dent Res. 2007; 86: 506-518
- Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression.J Neurosci. 2006; 26: 7281-7292
- RET signaling is required for survival and normal function of nonpeptidergic nociceptors.J Neurosci. 2010; 30: 3983-3994
- A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone.Cancer Res. 2005; 65: 9426-9435
- TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: Comparison with reference analgesics.Pain. 2002; 96: 99-105
- Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy.J Pain. 2008; 9: 463-472
- Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat.Neuroscience. 2010; 171: 344-350
- A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain.Neuroreport. 2001; 12: 3077-3080
- Nerve growth factor (NGF) and tyrosine kinase A (Trk A) receptor in oral squamous cell carcinoma: Is there an association with perineural invasion?.J Oral Maxillofac Surg. 2010; 68: 1290-1295
- Serine proteases and protease-activated receptor 2-dependent allodynia: A novel cancer pain pathway.Pain. 2010; 149: 263-272
- Spirocyclic delta opioid receptor agonists for the treatment of pain: Discovery of N, N-diethyl-3-hydroxy-4-(spiro[chromene-2,4’-piperidine]-4-yl) benzamide (ADL5747).J Med Chem. 2009; 52: 5685-5702
- VEGF and its receptor-2 involved in neuropathic pain transmission mediated by P2X2/3 receptor of primary sensory neurons.Brain Res Bull. 2010; 83: 284-291
- Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in glial cell line-derived neurotrophic factor family receptor alpha2 knock-out mice.J Neurosci. 2006; 26: 1953-1960
- Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia.Eur J Neurosci. 2005; 21: 3387-3394
- Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain.Neuroscience. 2010; 171: 588-598
- Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli.J Neurosci. 2005; 25: 9893-9901
- Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections.J Comp Neurol. 1995; 361: 404-416
- IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.Neuron. 1997; 19: 849-861
- Altered inflammatory gene expression underlies increased susceptibility to murine postoperative ileus with advancing age.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1650-G1659
- Delta-opioid receptor agonist SNC80 induces peripheral antinociception via activation of ATP-sensitive K+ channels.Eur J Pharmacol. 2005; 512: 23-28
- Delta-Opioid receptor agonist SNC80 elicits peripheral antinociception via delta(1) and delta(2) receptors and activation of the l-arginine/nitric oxide/cyclic GMP pathway.Life Sci. 2005; 78: 54-60
- Functional expression of thermo-transient receptor potential channels in dental primary afferent neurons: Implication for tooth pain.J Biol Chem. 2006; 281: 17304-17311
- Studies in vivo with dynorphin-(1-9): Analgesia but not gastrointestinal effects following intrathecal administration to mice.Eur J Pharmacol. 1983; 91: 291-294
- Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse.J Pain. 2007; 8: 263-272
- Endothelin-A receptor antagonism attenuates carcinoma-induced pain through opioids in mice.J Pain. 2010; 11: 663-671
- Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice.Pain. 2010; 149: 254-262
- Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.Cell. 2009; 137: 1148-1159
- Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization.Pain. 2005; 115: 128-141
- Problems of terminal head and neck cancer patients.Head Neck Surg. 1980; 2: 476-482
- Opioid regulation of mucosal ion transport in the mouse isolated jejunum.J Pharmacol Exp Ther. 1990; 253: 144-151
- Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: Identification of mu receptor-related functions.J Pharmacol Exp Ther. 1987; 242: 1-7
- Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: Relation of lectin reactivity to peptide and enzyme markers.J Neurocytol. 1990; 19: 789-801
- Tackling pain at the source: New ideas about nociceptors.Neuron. 1998; 20: 629-632
- Isolectin B(4)-positive and -negative nociceptors are functionally distinct.J Neurosci. 1999; 19: 6497-6505
- Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia.Pain. 2003; 104: 241-247
- The behavioral and neuroanatomical effects of IB4-saporin treatment in rat models of nociceptive and neuropathic pain.Brain Research. 2004; 1029: 65-76
- In vivo evidence for multiple opiate receptors mediating analgesia in the rat spinal cord.Brain Res. 1982; 247: 75-83
- Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF.J Physiol. 2004; 560: 391-401
- P2X3 is expressed by DRG neurons that terminate in inner lamina II.Eur J Neurosci. 1998; 10: 3470-3478
- Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons.Proc Natl Acad Sci U S A. 2010; 107: 13117-13122
- Nociceptors lacking TRPV1 and TRPV2 have normal heat responses.J Neurosci. 2004; 24: 6410-6415
- Nerve growth factor links oral cancer progression, pain, and cachexia.Mol Cancer Ther. 2011; 10: 1667-1676
- Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.J Clin Oncol. 1999; 17: 2419-2428
- Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse.J Neurosci. 2002; 22: 4057-4065
Article info
Publication history
Published online: April 09, 2012
Accepted:
January 16,
2012
Received in revised form:
January 2,
2012
Received:
August 2,
2011
Footnotes
This work was funded by NIH/NIDCR R21DE01856.
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.
