The dolognawmeter: A novel instrument and assay to quantify nociception in rodent models of orofacial pain
Introduction
More than 20% of adults are afflicted by orofacial pain (Lipton et al., 1993). Some of the most severe and difficult to treat forms of orofacial pain result from temporomandibular joint (TMJ) disorders, masticatory muscle inflammation and head and neck cancer. Patients with TMJ disorders or masticatory muscle inflammation report that chewing induces the highest levels of pain (Bush et al., 1989, Dworkin et al., 1990, Fricton et al., 1985, Gavish et al., 2000, Winocur et al., 2001, Zarb and Thompson, 1970). Patients with TMJ disorders experience significant and prolonged pain compared to normal subjects after chewing for an extended period of time (Karibe et al., 2003). In patients with masticatory myositis, jaw opening and closing while chewing significantly exacerbates muscle pain (Bowley and Gale, 1987, Christensen, 1976, Christensen and Radue, 1985, Dao et al., 1994, Molin, 1972, Plesh et al., 1998, Scott and Lundeen, 1980). Duration of chewing is associated with development of pain. Patients with TMJ and masticatory muscle pain experience a significant increase in pain after chewing for 9 min (Gavish et al., 2002). The American Academy of Orofacial Pain recommends resting the jaw and limiting jaw movement in patients with TMJ or masticatory muscle pain (Pain).
Like joint and muscle disorders, head and neck cancer causes functional allodynia (Connelly and Schmidt, 2004, Kolokythas et al., 2007). Patients with head and neck cancer report pain as the worst symptom (Shedd et al., 1980), and the primary determinant of a poor quality of life (Chaplin and Morton, 1999, Hodder et al., 1997). In their final months of life 85% of these patients report pain as the most common problem (Shedd et al., 1980). Half of all head and neck cancers are incurable and many patients suffer from intractable cancer pain for extended periods. Oral cancer patients experience significant debilitation of chewing and oral function secondary to pain (Connelly and Schmidt, 2004, Rogers et al., 2006). To investigate orofacial pain ultimately develop treatments for patients we have created an assay that elicits and measures pain-induced oral dysfunction in an animal model.
Masticatory dysfunction is one of the hallmarks of orofacial pain. An objective animal assay that quantifies nociception-induced dysfunction, as seen clinically, is not available. We hypothesize that nociception-induced gnawing dysfunction can be used as an index of orofacial nociception in an animal model. Gnawing involves incisor occlusion and molar disclusion but shares nearly all of the anatomical and physiological components of chewing in humans. To test our hypothesis we designed and validated a novel assay and device (a dolognawmeter-dolor for pain, gnawmeter for measurement of gnawing) that together objectively quantify gnawing function in mice. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer.
Section snippets
Design of the dolognawmeter
The dolognawmeter is designed for high throughput. Experimental productivity is limited only by the number of devices employed. A dolognawmeter is fabricated as described below (Fig. 1, Fig. 2).
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The confinement tube is manufactured from a 180 mm section of commercially available schedule-80 polyvinyl chloride (PVC) tubing with an internal diameter of 24 mm and an external diameter of 33 mm. A set of radially oriented holes is drilled entirely through the tube at 30 mm and 50 mm from the end of the
TMJ inflammatory pain model
CFA injection into the left TMJ produced a mean 567.0 ± 273.8 (SEM) % increase in gnaw time compared to the TMJ saline-injected model at 10 and 58 h following injection (Fig. 3). Pretreatment with indomethacin prevented the increase in gnaw time seen in animals receiving only CFA injection into the left TMJ (Fig. 3). Histologic evaluation of the TMJ demonstrated that CFA injection produced an inflammatory infiltrate (Fig. 4a) while saline injection into the TMJ did not (Fig. 4b).
Masticatory muscle inflammatory pain model
The masseter
Discussion
We developed a high throughput, objective, operant assay for orofacial function and validated its ability to detect acute and chronic functional allodynia. The dolognawmeter quantified a behavioral index of nociception in three separate mouse models of orofacial pain (TMJ inflammation, masticatory myositis and head and neck cancer). To confirm that the behavioral dependent measure (gnaw time) reflects nociception, we restored gnawing function by blocking nociception with the same analgesics
Acknowledgment
Supported by NIH/NIDCR R21 DE018561.
References (43)
- et al.
Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain related behavior in rats
Life Sci
(1978) - et al.
Gnawing behavior of a mouse in a narrow cylinder: a simple system for the study of muscle activity, fatigue, and stress
Physiol Behav
(2002) - et al.
Evaluation of pain in patients with oral squamous cell carcinoma
J Pain
(2004) - et al.
Epidemiology of signs and symptoms in temporomandibular disorders: clinical signs in cases and controls
J Am Dent Assoc
(1990) - et al.
Myofascial pain syndrome of the head and neck: a review of clinical characteristics of 164 patients
Oral Surg Oral Med Oral Pathol
(1985) - et al.
Modulation of the inflammatory response in the rat TMJ with increasing doses of complete Freund's adjuvant
Osteoarthritis Cartilage
(2001) - et al.
Inflammation increases the excitability of masseter muscle afferents
Neuroscience
(2006) - et al.
Calcitonin gene-related peptide and substance P immunoreactivity in rat trigeminal ganglia and brainstem following adjuvant-induced inflammation of the temporomandibular joint
Arch Oral Biol
(2000) - et al.
A new animal model for assessing mechanisms and management of muscle hyperalgesia
Pain
(2000) - et al.
Specificity of meal pattern analysis as an animal model of determining temporomandibular joint inflammation/pain
Int J Oral Maxillofac Surg
(2005)
Validation of the university of California San Francisco oral cancer pain questionnaire
J Pain
Estimated prevalence and distribution of reported orofacial pain in the United States
J Am Dent Assoc
The effect of MK-801 and SCH23390 on the expression and sensitization of morphine-induced oral stereotypy
Brain Res
Characterization of a model of chronic orofacial hyperalgesia in the rat: contribution of NA(V) 1.8
J Pain
Expression of integrin beta-6 enhances invasive behavior in oral squamous cell carcinoma
Matrix Biol
Health-related quality of life measured by the UW-QoL—reference values from a general dental practice
Oral Oncol
Development of a behavioral model of TMJ pain in rats: the TMJ formalin test
Pain
Peripheral endothelin A receptor antagonism attenuates carcinoma-induced pain
Eur J Pain
Myofascial pain involving the masticatory muscles: an experimental model
Pain
Rat knee-joint carrageenin incapacitation test: an objective screen for central and peripheral analgesics
Pain
Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints
Pain
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